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Direct chemically mediated synaptic transmission from mechanosensory afferents contributes to habituation of crayfish lateral giant escape reaction
M. Araki; T. Nagayama
The neural mechanism of habituation of the crayfish lateral giant-mediated escape reaction was analyzed electrophysiologically and pharmacologically. Upon repeated stimulation of tailfan afferents (at 0.2–1 Hz) lateral giant showed rapid habituation and failed to spike. Upon low-intensity sensory stimulation, the lateral giant responded with two subthreshold excitatory post-synaptic potentials, the a and ß components. A third component, the a' component, was
Activation of transient receptor potential vanilloid 2-expressing primary afferents stimulates synaptic transmission in the deep dorsal horn of the rat spinal cord and elicits mechanical hyperalgesia.
Petitjean, Hugues; Hugel, Sylvain; Barthas, Florent; Bohren, Yohann; Barrot, Michel; Yalcin, Ipek; Schlichter, Rémy
Probenecid, an agonist of transient receptor vanilloid (TRPV) type 2, was used to evaluate the effects of TRPV2 activation on excitatory and inhibitory synaptic transmission in the dorsal horn (DH) of the rat spinal cord and on nociceptive reflexes induced by thermal heat and mechanical stimuli. The effects of probenecid were compared with those of capsaicin, a TRPV1 agonist. Calcium imaging experiments on rat dorsal root ganglion (DRG) and DH cultures indicated that functional TRPV2 and TRPV1 were expressed by essentially non-overlapping subpopulations of DRG neurons, but were absent from DH neurons and DH and DRG glial cells. Pretreatment of DRG cultures with small interfering RNAs against TRPV2 suppressed the responses to probenecid. Patch-clamp recordings from spinal cord slices showed that probenecid and capsaicin increased the frequencies of spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents in a subset of laminae III-V neurons. In contrast to capsaicin, probenecid failed to stimulate synaptic transmission in lamina II. Intrathecal or intraplantar injections of probenecid induced mechanical hyperalgesia/allodynia without affecting nociceptive heat responses. Capsaicin induced both mechanical hyperalgesia/allodynia and heat hyperalgesia. Activation of TRPV1 or TRPV2 in distinct sets of primary afferents increased the sEPSC frequencies in a largely common population of DH neurons in laminae III-V, and might underlie the development of mechanical hypersensitivity following probenecid or capsaicin treatment. However, only TRPV1-expressing afferents facilitated excitatory and/or inhibitory transmission in a subpopulation of lamina II neurons, and this phenomenon might be correlated with the induction of thermal heat hyperalgesia. PMID:25104469
Inhibition by efferent nerve fibres: action on hair cells and afferent synaptic transmission in the lateral line canal organ of the burbot Lota lota.
Flock, A; Russell, I
1. Intracellular recordings were made from morphologically identified hair cells in the lateral line canal organs of the burbot Lota lota. 2. I.p.s.p.s were recorded from hair cells when the efferent fibres were excited by electrical stimulation of the lateral line nerve. The i.p.s.p.s were abolished when the fish was injected with immobilizing concentration of Flaxedil which is known to block the efferent synapses. 3. The i.p.s.p.s are accompanied by a decrease in the resistance of the hair cell membrane and an increase in the intracellular receptor potential. 4. Spontaneous and mechanically evoked e.p.s.p.s which were recorded intracellularly from the post-synaptic afferent nerve terminals were reduced in amplitude for the duration of the i.p.s.p. Images A, B C PMID:948076
Astrocytes Potentiate Synaptic Transmission
NASA Astrophysics Data System (ADS)
Nadkarni, Suhita
A recent experimental study shows that astrocytes, a subtype of glia, are able to influence the spontaneous activity in the brain via calcium dependent glutamate release. We model the coupling mechanism between an astrocyte and a neuron based on experimental data. This coupling is dynamic and bi-directional, such that the modulations in intracellular calcium concentrations in astrocytes affect neuronal excitability and vice versa via a glutamatergic pathway. We demonstrate through simple neural-glial circuits that increases in the intracellular calcium concentration in astrocytes nearby can enhance spontaneous activity in a neuron, a significant mechanism said to be involved in plasticity and learning. The pattern of this marked increase in spontaneous firing rate in our model quantitatively follows that observed in the experiment. Further, depending on the type of synaptic connections diverging from the neuron, it can either inhibit or excite the ensuing dynamics and potentiate synaptic transmission, thus reinstating the integral role played by astrocytes in normal neuronal dynamics.
Nicotinic modulation of glutamatergic synaptic transmission in region CA3 of the hippocampus
Hasselmo, Michael
Nicotinic modulation of glutamatergic synaptic transmission in region CA3 of the hippocampus Lisa M, hippocampus, memory, nicotine Abstract Cholinergic modulation of synaptic transmission in the hippocampus of hippocampal region CA3, we have explored the effect of nicotine on the afferent connections of stratum
A Positive Allosteric Modulator of the Adenosine A1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model.
Imlach, Wendy L; Bhola, Rebecca F; May, Lauren T; Christopoulos, Arthur; Christie, Macdonald J
In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A1 receptor (A1R), resulting in antinociception and highlighting the potential of therapeutically targeting the receptor in the treatment of neuropathic pain. This study investigated the changes in adenosine tone and A1R signaling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171 [(2-amino-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone], on excitatory and inhibitory neurotransmission at spinal cord superficial dorsal horn synapses in a rat partial nerve-injury model of neuropathic pain. In the absence of A1R agonists, superfusion of the A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 ?M), produced a significantly greater increase in electrically evoked ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic current (eEPSC) amplitude in both lamina I and II neurons from nerve-injured animals than in controls, suggesting that endogenous adenosine tone is increased in the dorsal horn. Inhibitory GABAergic and glycinergic synaptic currents were also significantly increased by DPCPX in controls but there was no difference after nerve injury. The A1R agonist, N6-cyclopentyladenosine, produced greater inhibition of eEPSC amplitude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus control animals, suggesting a functional increase in A1R sensitivity in lamina II neurons after nerve injury. The A1R PAM, VCP171, produced a greater inhibition of eEPSC amplitude of nerve-injury versus control animals in both lamina I and lamina II neurons. Enhanced adenosine tone and A1R sensitivity at excitatory synapses in the dorsal horn after nerve injury suggest that new generation PAMs of the A1R can be effective treatments for neuropathic pain. PMID:26104547
Synaptic transmission and transporters
Alford, Simon
, the transmitters bind to and activate receptors in the postsynaptic membrane. · Ionotropic (ligand-gated) receptor vertebrates · Chemical synapses Chemical released by presynaptic cells bind to receptors on postsynaptic into synaptic cleft, they bind to specific protein molecules, receptors, in the membrane of the postsynaptic
Role of capsaicin-sensitive C-fiber afferents in neuropathic pain-induced synaptic potentiation in the nociceptive amygdala
Background Neurons in the capsular part of the central nucleus of the amygdala (CeC), a region also called "nociceptive amygdala," receive nociceptive information from the dorsal horn via afferent pathways relayed from the lateral parabrachial nucleus (LPB). As the central amygdala is known to be involved in the acquisition and expression of emotion, this pathway is thought to play central roles in the generation of affective responses to nociceptive inputs. Excitatory synaptic transmission between afferents arising from the LPB and these CeC neurons is potentiated in arthritic, visceral, neuropathic, inflammatory and muscle pain models. In neuropathic pain models following spinal nerve ligation (SNL), in which we previously showed a robust LPB-CeC potentiation, the principal behavioral symptom is tactile allodynia triggered by non-C-fiber low-threshold mechanoreceptor afferents. Conversely, recent anatomical studies have revealed that most of the spinal neurons projecting to the LPB receive C-fiber afferent inputs. Here, we examined the hypothesis that these C-fiber-mediated inputs are necessary for the full establishment of robust synaptic potentiation of LPB-CeC transmission in the rats with neuropathic pain. Results Postnatal capsaicin treatment, which has been shown to denervate the C-fibers expressing transient receptor potential vanilloid type-1 (TRPV1) channels, completely abolished eye-wiping responses to capsaicin eye instillation in rats, but this treatment did not affect mechanical allodynia in the nerve-ligated animals. However, the postnatal capsaicin treatment prevented LPB-CeC synaptic potentiation after SNL, unlike in the vehicle-treated rats, primarily due to the decreased incidence of potentiated transmission by elimination of TRPV1-expressing C-fiber afferents. Conclusions C-fiber-mediated afferents in the nerve-ligated animals may be a required facilitator of the establishment of nerve injury-evoked synaptic potentiation in the CeC. These inputs might play essential roles in the chronic pain-induced plastic changes in the central network linking nociception and negative emotion. PMID:22776418
TRPV1 Marks Synaptic Segregation of Multiple Convergent Afferents at the Rat Medial Solitary Tract Nucleus
Peters, James H.; McDougall, Stuart J.; Fawley, Jessica A.; Andresen, Michael C.
TRPV1 receptors are expressed on most but not all central terminals of cranial visceral afferents in the caudal solitary tract nucleus (NTS). TRPV1 is associated with unmyelinated C-fiber afferents. Both TRPV1+ and TRPV1- afferents enter NTS but their precise organization remains poorly understood. In horizontal brainstem slices, we activated solitary tract (ST) afferents and recorded ST-evoked glutamatergic excitatory synaptic currents (ST-EPSCs) under whole cell voltage clamp conditions from neurons of the medial subnucleus. Electrical shocks to the ST produced fixed latency EPSCs (jitter<200 µs) that identified direct ST afferent innervation. Graded increases in shock intensity often recruited more than one ST afferent and ST-EPSCs had consistent threshold intensity, latency to onset, and unique EPSC waveforms that characterized each unitary ST afferent contact. The TRPV1 agonist capsaicin (100 nM) blocked the evoked TRPV1+ ST-EPSCs and defined them as either TRPV1+ or TRPV1- inputs. No partial responses to capsaicin were observed so that in NTS neurons that received one or multiple (2–5) direct ST afferent inputs – all were either blocked by capsaicin or were unaltered. Since TRPV1 mediates asynchronous release following TRPV1+ ST-evoked EPSCs, we likewise found that recruiting more than one ST afferent further augmented the asynchronous response and was eliminated by capsaicin. Thus, TRPV1+ and TRPV1- afferents are completely segregated to separate NTS neurons. As a result, the TRPV1 receptor augments glutamate release only within unmyelinated afferent pathways in caudal medial NTS and our work indicates a complete separation of C-type from A-type afferent information at these first central neurons. PMID:21949835
Synaptic Transmission Correlates of General Mental Ability
ERIC Educational Resources Information Center
McRorie, Margaret; Cooper, Colin
Nerve conduction velocity (NCV) and efficiency of synaptic transmission are two possible biological mechanisms that may underpin intelligence. Direct assessments of NCV, without synaptic transmission, show few substantial or reliable correlations with cognitive abilities ["Intelligence" 16 (1992) 273]. We therefore assessed the latencies of…
Synaptic inputs to trigeminal primary afferent neurons cause firing and modulate intrinsic oscillatory activity.
Verdier, Dorly; Lund, James P; Kolta, Arlette
In this paper, we investigated the influence of synapses on the cell bodies of trigeminal muscle spindle afferents that lie in the trigeminal mesencephalic nucleus (NVmes), using intracellular recordings in brain stem slices of young rats. Three types of synaptic responses could be evoked by electrical stimulation of the adjacent supratrigeminal, motor, and main sensory nuclei and the intertrigeminal area: monophasic depolarizing postsynaptic potentials (PSPs), biphasic PSPs, and all or none action potentials without underlying excitatory PSPs (EPSPs). Many PSPs and spikes were abolished by bath-application of 6,7-dinitroquinoxaline (DNQX) alone or combined with D,L-2-amino-5-phosphonovaleric acid (APV), suggesting that they are mediated by non-N-methyl-D-aspartate (NMDA) and NMDA glutamatergic receptors, while some action potentials were sensitive to bicuculline, indicating involvement of GABAA receptors. A number of cells showed spontaneous membrane potential oscillations, and stimulation of synaptic inputs increased the amplitude of the oscillations for several cycles, which often triggered repetitive firing. Furthermore, the oscillatory rhythm was reset by the stimulation. Our results show that synaptic inputs to muscle primary afferent neurons in NVmes from neighboring areas are mainly excitatory and that they cause firing. In addition, the inputs synchronize intrinsic oscillations, which may lead to sustained, synchronous firing in a subpopulation of afferents. This may be of importance during rapid biting and during the mastication of very hard or tough foods. PMID:15381749
Mannose-Specific Recognition Mediates Two Aspects of Synaptic Growth of Leech Sensory Afferents: Collateral Branching and Proliferation of Synaptic Vesicle Clusters
Mei-Hui Tai; Birgit Zipser
The developmental role of carbohydrate markers in the genesis of neuronal networks was studied using leech sensory afferents as a model. Leech sensory afferents express a mannose-containing epitope on their cell surface that is recognized by monoclonal antibody Lan3-2. Previously, the elaboration of sensory arbors in the synaptic neuropil of CNS ganglia was experimentally shown to depend on this mannose
Development of Synaptic Transmission to Respiratory Motoneurons
Berger, Albert J.
Respiratory motoneurons provide the exclusive drive to respiratory muscles and therefore are a key relay between brainstem neural circuits that generate respiratory rhythm and respiratory muscles that control moment of gases into and out of the airways and lungs. This review is focused on postnatal development of fast ionotropic synaptic transmission to respiratory motoneurons, with a focus on hypoglossal motoneurons (HMs). Glutamatergic synaptic transmission to HMs involves activation of both non-NMDA and NMDA receptors and during the postnatal period co-activation of these receptors located at the same synapse may occur. Further, the relative role of each receptor type in inspiratory-phase motoneuron depolarization is dependent on the type of preparation used (in vitro versus in vivo; neonatal versus adult). Respiratory motoneurons receive both glycinergic and GABAergic inhibitory synaptic inputs. During inspiration phrenic and HMs receive concurrent excitatory and inhibitory synaptic inputs. During postnatal development in HMs GABAergic and glycinergic synaptic inputs have slow kinetics and are depolarizing and with postnatal development they become faster and hyperpolarizing. Additionally shunting inhibition may play an important role in synaptic processing by respiratory motoneurons. PMID:21382524
Transient analysis of a chemical synaptic transmission
Dmitriy Melkonian
The statistical dynamics of an impulse induced quanta turnover is studied by means of a nonstationary stochastic model — double barrier synapse — resulting from a previously developed mathematical theory of chemical synaptic transmission. An essential aspect of nonstationarities of the model is that the interpool quanta transfers follow binomial distribution at impulse arrival time, while in the absence of
Psychostimulants Depress Excitatory Synaptic Transmission in the Nucleus Accumbens via Presynaptic Dl Like Dopamine Receptors
Saleem M. Nicola; Samuel B. Kombian; Robert C. Malenka
The effects of dopamine (DA) and the psychostimulants cocaine and amphetamine on excitatory transmission in the nucleus accumbens (NAc) were examined in rat NAc slices using both extracellular-field and whole-cell patch-clamp recording. DA, cocaine, and amphetamine reversibly reduced the excitatory synaptic responses (EPSPs\\/EPSCs) elicited by stimulation of prelimbic cortical afferents. DA and amphetamine increased paired-pulse facilitation, reduced the frequency of
Synaptic GluN2A and GluN2B Containing NMDA Receptors within the Superficial Dorsal Horn Activated following Primary Afferent Stimulation
MacDermott, Amy B.
NMDA receptors are important elements in pain signaling in the spinal cord dorsal horn. They are heterotetramers, typically composed of two GluN1 and two of four GluN2 subunits: GluN2A-2D. Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved. In this study, we have investigated the composition of synaptic NMDA receptors expressed in monosynaptic and polysynaptic pathways from peripheral sensory fibers to lamina I neurons in rats. We focused on substance P receptor-expressing (NK1R+) projection neurons, critical for expression of hyperalgesia and allodynia. EAB-318 and (R)-CPP, GluN2A/B antagonists, blocked both monosynaptic and polysynaptic NMDA EPSCs initiated by primary afferent activation by ?90%. Physiological measurements exploiting the voltage dependence of monosynaptic EPSCs similarly indicated dominant expression of GluN2A/B types of synaptic NMDA receptors. In addition, at synapses between C fibers and NK1R+ neurons, NMDA receptor activation initiated a secondary, depolarizing current. Ifenprodil, a GluN2B antagonist, caused modest suppression of monosynaptic NMDA EPSC amplitudes, but had a widely variable, sometimes powerful, effect on polysynaptic responses following primary afferent stimulation when inhibitory inputs were blocked to mimic neuropathic pain. We conclude that GluN2B subunits are moderately expressed at primary afferent synapses on lamina I NK1R+ neurons, but play more important roles for polysynaptic NMDA EPSCs driven by primary afferents following disinhibition, supporting the view that the analgesic effect of the GluN2B antagonist on neuropathic pain is at least in part, within the spinal cord. PMID:25122884
Synaptic GluN2A and GluN2B containing NMDA receptors within the superficial dorsal horn activated following primary afferent stimulation.
Tong, Chi-Kun; MacDermott, Amy B
NMDA receptors are important elements in pain signaling in the spinal cord dorsal horn. They are heterotetramers, typically composed of two GluN1 and two of four GluN2 subunits: GluN2A-2D. Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved. In this study, we have investigated the composition of synaptic NMDA receptors expressed in monosynaptic and polysynaptic pathways from peripheral sensory fibers to lamina I neurons in rats. We focused on substance P receptor-expressing (NK1R+) projection neurons, critical for expression of hyperalgesia and allodynia. EAB-318 and (R)-CPP, GluN2A/B antagonists, blocked both monosynaptic and polysynaptic NMDA EPSCs initiated by primary afferent activation by ?90%. Physiological measurements exploiting the voltage dependence of monosynaptic EPSCs similarly indicated dominant expression of GluN2A/B types of synaptic NMDA receptors. In addition, at synapses between C fibers and NK1R+ neurons, NMDA receptor activation initiated a secondary, depolarizing current. Ifenprodil, a GluN2B antagonist, caused modest suppression of monosynaptic NMDA EPSC amplitudes, but had a widely variable, sometimes powerful, effect on polysynaptic responses following primary afferent stimulation when inhibitory inputs were blocked to mimic neuropathic pain. We conclude that GluN2B subunits are moderately expressed at primary afferent synapses on lamina I NK1R+ neurons, but play more important roles for polysynaptic NMDA EPSCs driven by primary afferents following disinhibition, supporting the view that the analgesic effect of the GluN2B antagonist on neuropathic pain is at least in part, within the spinal cord. PMID:25122884
The Neurobiology of Slow Synaptic Transmission
Paul Greengard
Nerve cells communicate with each other through two mechanisms, referred to as fast and slow synaptic transmission. Fast-acting neurotransmitters, e.g., glutamate (excitatory) and gamma-aminobutyric acid (GABA) (inhibitory), achieve effects on their target cells within one millisecond by virtue of opening ligand-operated ion channels. In contrast, all of the effects of the biogenic amine and peptide neurotransmitters, as well as many
Sequential Steps in Synaptic Targeting of Sensory Afferents Are Mediated by Constitutive and Developmentally Regulated Glycosylations of CAMs
Mei-Hui Tai; Birgit Zipser
Sensory afferents in the leech are labeled with both constitutive and developmentally regulated glycosylations (markers) of their cell adhesion molecules (CAMs). Their constitutive mannose marker, recognized by Lan3-2 monoclonal antibody (mAb), mediates the formation of their diffuse central arbors. We show that, at the ultrastructural level, these arbors consist of large, loosely organized axons rich with filopodia and synaptic vesicles.
Control of Neural Information Transmission by Synaptic Dynamics
The computational processing of a neural system is strongly influenced by the dynamical characteristics of the information transmission between neurons. In this work, the control of neural information transmission by synaptic dynamics is investigated by means of a master-equation-based stochastic model of pre-synaptic release of neurotransmitter-containing vesicles. The model incorporates facilitation of vesicle fusion with the pre-synaptic membrane due to
Homeostasis of Synaptic Transmission in Drosophila with Genetically Altered Nerve Terminal Morphology
Stewart, Bryan
Homeostasis of Synaptic Transmission in Drosophila with Genetically Altered Nerve Terminal through analy- sis of synaptic transmission at Drosophila neuromuscular junc- tions with a genetically for genetic perturbations, thereby maintaining optimal syn- aptic transmission. Key words: synaptic
Laminar Selectivity of the Cholinergic Suppression of Synaptic Transmission in Rat Hippocampal Region CA 1: Computational Modeling and Brain Slice Physiology
Michael E. Hasselmo; Eric Schnell
ACh may set the dynamics of cortical function to those ap- propriate for learning new information. In models of the pu- tative associative memory function of piriform cortex, se- lective suppression of intrinsic but not afferent fiber synaptic transmission by ACh prevents recall of previous input from interfering with the learning of new input (Hasselmo, 1993). Selective cholinergic suppression may
Evidence that large myelinated primary afferent fibers make synaptic contacts in lamina II of neonatal rats
Richard E. Coggeshall; Ernest A. Jennings; Maria Fitzgerald
Choleragenoid horseradish peroxidase (B-HRP) is a retrogradely transported marker that selectively labels large cutaneous myelinated primary afferent fibers. In adults, B-HRP labelled large afferent fibers are seen to enter laminae III–V, and to a lesser extent lamina I, whereas lamina II, which is the major termination site of unmyelinated primary afferents, remains unlabelled. In the neonate, however, there is extensive
New roles for astrocytes: Regulation of synaptic transmission
Newman, Eric A.
New roles for astrocytes: Regulation of synaptic transmission Eric A. Newman Department with the synaptic structure. In the cortex, synapses are ensheathed by processes of astrocytes, the most common type of glial cell in the brain [1,2]. Synapses in the cerebellum are enveloped by Bergmann glia (specialized
Synaptic unreliability facilitates information transmission in balanced cortical populations
NASA Astrophysics Data System (ADS)
Gatys, Leon A.; Ecker, Alexander S.; Tchumatchenko, Tatjana; Bethge, Matthias
Synaptic unreliability is one of the major sources of biophysical noise in the brain. In the context of neural information processing, it is a central question how neural systems can afford this unreliability. Here we examine how synaptic noise affects signal transmission in cortical circuits, where excitation and inhibition are thought to be tightly balanced. Surprisingly, we find that in this balanced state synaptic response variability actually facilitates information transmission, rather than impairing it. In particular, the transmission of fast-varying signals benefits from synaptic noise, as it instantaneously increases the amount of information shared between presynaptic signal and postsynaptic current. Furthermore we show that the beneficial effect of noise is based on a very general mechanism which contrary to stochastic resonance does not reach an optimum at a finite noise level.
Synaptic transmission block by presynaptic injection of oligomeric amyloid beta.
Moreno, Herman; Yu, Eunah; Pigino, Gustavo; Hernandez, Alejandro I; Kim, Natalia; Moreira, Jorge E; Sugimori, Mutsuyuki; Llinás, Rodolfo R
Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Abeta42, but not oAbeta40 or extracellular oAbeta42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAbeta42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD. PMID:19304802
Estrogen facilitates spinal cord synaptic transmission via membrane-bound estrogen receptors: implications for pain hypersensitivity.
Zhang, Yan; Xiao, Xiao; Zhang, Xiao-Meng; Zhao, Zhi-Qi; Zhang, Yu-Qiu
Recent evidence suggests that estrogen is synthesized in the spinal dorsal horn and plays a role in nociceptive processes. However, the cellular and molecular mechanisms underlying these effects remain unclear. Using electrophysiological, biochemical, and morphological techniques, we here demonstrate that 17?-estradiol (E2), a major form of estrogen, can directly modulate spinal cord synaptic transmission by 1) enhancing NMDA receptor-mediated synaptic transmission in dorsal horn neurons, 2) increasing glutamate release from primary afferent terminals, 3) increasing dendritic spine density in cultured spinal cord dorsal horn neurons, and 4) potentiating spinal cord long term potentiation (LTP) evoked by high frequency stimulation (HFS) of Lissauer's tract. Notably, E2-BSA, a ligand that acts only on membrane estrogen receptors, can mimic E2-induced facilitation of HFS-LTP, suggesting a nongenomic action of this neurosteroid. Consistently, cell surface biotinylation demonstrated that three types of ERs (ER?, ER?, and GPER1) are localized on the plasma membrane of dorsal horn neurons. Furthermore, the ER? and ER? antagonist ICI 182,780 completely abrogates the E2-induced facilitation of LTP. ER? (but not ER?) activation can recapitulate E2-induced persistent increases in synaptic transmission (NMDA-dependent) and dendritic spine density, indicating a critical role of ER? in spinal synaptic plasticity. E2 also increases the phosphorylation of ERK, PKA, and NR2B, and spinal HFS-LTP is prevented by blockade of PKA, ERK, or NR2B activation. Finally, HFS increases E2 release in spinal cord slices, which can be prevented by aromatase inhibitor androstatrienedione, suggesting activity-dependent local synthesis and release of endogenous E2. PMID:22869379
Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex
ERIC Educational Resources Information Center
Linster, Christiane; Menon, Alka V.; Singh, Christopher Y.; Wilson, Donald A.
Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between…
Measuring action potential-evoked transmission at individual synaptic contacts
Nauen, David W; Bi, Guo-Qiang
In the neuronal culture experimental system, the total synaptic connection between two neurons can consist of large numbers of synaptic sites, each behaving probabilistically. Studies of synaptic function with paired recordings typically consider the summed response across all of these sites and from this infer the average response. Understanding of synaptic transmission and plasticity could be improved by examination of activity at as few synaptic sites as possible. To this end, we develop a system for recording responses from individual contacts. It relies on a precisely regulated pneumatic/hydrostatic pressure system to create a microenvironment within which individual synapses are active, and an acoustic signature method to monitor the stability of this microenvironment noninvasively. With this method we are able to record action potential-evoked postsynaptic currents consistent with individual quanta. The approach does not distort synaptic current waveforms and permits stable recording for several hours. The method is applied to address mechanisms of short-term plasticity, the variability of latency at individual synaptic sites and, in a preliminary experiment, the independence of nearby synapses on the same axon. PMID:22626987
Scaffold remodeling in space and time controls synaptic transmission
Perroy, Julie; Moutin, Enora
Scaffolding proteins that are associated with glutamate receptors in dendritic spines govern the location and function of receptors to control synaptic transmission. Unraveling the spatio-temporal dynamics of protein-protein interactions within components of the scaffolding complex will bring to light the function of these interactions. Combining bioluminescence resonance energy transfer (BRET) imaging to electrophysiological recordings, we have recently shown that GKAP, a core protein of the scaffolding complex, interacts with DLC2, a protein associated with molecular motors. Synaptic activity-induced GKAP-DLC2 interaction in spines stabilizes the scaffolding complex and enhances the NMDA currents. Interestingly, this work placed emphasis on the bioarchitectural dependence of protein-protein interaction dynamics. Depending on physiological conditions, the modulation in space and time of protein-protein interaction is acutely regulated, engendering a subtle control of synaptic transmission in the state of the individual synapse. PMID:22754626
Calcium-dependent synaptic vesicle trafficking underlies indefatigable release at the hair cell afferent fiber synapse
Schnee, M.E.; Santos-Sacchi, J.; Castellano-Muńoz, M.; Kong, J-H.; Ricci, A.J.
Sensory hair cell ribbon synapses respond to graded stimulation in a linear, indefatigable manner, requiring that vesicle trafficking to synapses is rapid and non rate limiting. Real time monitoring of vesicle fusion identified two release components. The first was saturable with both release rate and magnitude varying linearly with Ca2+, however the magnitude was too small to account for sustained afferent firing rates. A second superlinear release component required recruitment, in a Ca2+-dependent manner, of vesicles not in the immediate vicinity of the synapse. The superlinear component had a constant rate with its onset varying with Ca2+ load. High-speed Ca2+ imaging revealed a nonlinear increase in internal Ca2+ correlating with the superlinear capacitance change, implicating release of stored Ca2+ in driving vesicle recruitment. These data, supported by a mass action model, suggest sustained release at hair cell afferent fiber synapse is dictated by Ca2+-dependent vesicle recruitment from a reserve pool. PMID:21521617
Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants
Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.
Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) ? subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called 'accordion' phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the 'twitch-once' phenotype. We review current knowledge regarding zebrafish 'accordion' and 'twitch-once' mutants, including beo and sho, and report the identification of a new ?2 subunit that revises the phylogeny of zebrafish GlyRs. PMID:20161699
Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus
ERIC Educational Resources Information Center
Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.
Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…
Rescue of tau-induced synaptic transmission pathology by paclitaxel
Erez, Hadas; Shemesh, Or A.; Spira, Micha E.
Behavioral and electrophysiological studies of Alzheimer's disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as extracellular amyloid-? plaques, intracellular hyperphosphorylated tau or neuronal loss. Recent experiments have also demonstrated that anti-cancer microtubule (MT)-stabilizing drugs can rescue tau-induced behavioral decline and hallmark neuron pathologies. Nevertheless, the mechanisms underlying tau-induced synaptic dysfunction as well as those involved in the rescue of cognitive decline by MTs-stabilizing drugs remain unclear. Here we began to study these mechanisms using the glutaminergic sensory-motoneuron synapse derived from Aplysia ganglia, electrophysiological methods, the expression of mutant-human tau (mt-htau) either pre or postsynaptically and the antimitotic drug paclitaxel. Expression of mt-htau in the presynaptic neurons led to reduced excitatory postsynaptic potential (EPSP) amplitude generated by rested synapses within 3 days of mt-htau expression, and to deeper levels of homosynaptic depression. mt-htau-induced synaptic weakening correlated with reduced releasable presynaptic vesicle pools as revealed by the induction of asynchronous neurotransmitter release by hypertonic sucrose solution. Paclitaxel totally rescued tau-induced synaptic weakening by maintaining the availability of the presynaptic vesicle stores. Postsynaptic expression of mt-htau did not impair the above described synaptic-transmission parameters for up to 5 days. Along with earlier confocal microscope observations from our laboratory, these findings suggest that tau-induced synaptic dysfunction is the outcome of impaired axoplasmic transport and the ensuing reduction in the releasable presynaptic vesicle stores rather than the direct effects of mt-htau or paclitaxel on the synaptic release mechanisms. PMID:24574970
MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity
Zhu Guoqi; Chen Ying; Huang Yuying [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); Li Qinglin [Key laboratory of XinAn Medicine, Anhui University of Traditional Chinese Medicine, Hefei 230038 (China); Behnisch, Thomas, E-mail: email@example.com [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China)
Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: > I.p. MPTP-injection mediates death of dopaminergic neurons. > I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. > I.p. MPTP-injection does not alter basal synaptic transmission. > Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. > Attenuation of NMDA-receptors mediated fEPSPs after i.p. MPTP-injection.
Cyclic AMP and Afferent Activity Govern Bidirectional Synaptic Plasticity in Striatopallidal Neurons
Augustin, Shana M.; Beeler, Jeff A.; Zhuang, Xiaoxi
Recent experimental evidence suggests that the low dopamine conditions in Parkinson's disease (PD) cause motor impairment through aberrant motor learning. Those data, along with computational models, suggest that this aberrant learning results from maladaptive corticostriatal plasticity and learned motor inhibition. Dopaminergic modulation of both corticostriatal long-term depression (LTD) and long-term potentiation (LTP) is proposed to be critical for these processes; however, the regulatory mechanisms underlying bidirectional corticostriatal plasticity are not fully understood. Previously, we demonstrated a key role for cAMP signaling in corticostriatal LTD. In this study, mouse brain slices were used to perform a parametric experiment that tested the impact of varying both intracellular cAMP levels and the strength of excitatory inputs on corticostriatal plasticity. Using slice electrophysiology in the dorsolateral striatum, we demonstrate that both LTP and LTD can be sequentially induced in the same D2-expressing neuron and that LTP was strongest with high intracellular cAMP and LFS, whereas LTD required low intracellular cAMP and high-frequency stimulation. Our results provide a molecular and cellular basis for regulating bidirectional corticostriatal synaptic plasticity and may help to identify novel therapeutic targets for blocking or reversing the aberrant synaptic plasticity that likely contributes to motor deficits in PD. PMID:24806695
How do astrocytes shape synaptic transmission? Insights from electrophysiology
Dallérac, Glenn; Chever, Oana; Rouach, Nathalie
A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy. PMID:24101894
Presynaptic Actions of Carbachol and Adenosine on Corticostriatal Synaptic Transmission Studied in vitro
Robert C. Malenka; Jeffery D. Kocsis
The purpose of this study was to identify, in the in vitro rat neostriatal slice preparation, an electrophysiological re- sponse corresponding to the activation of striatal neurons by cortical afferents, and to study the actions of a variety of putative neurotransmitters on modulating synaptic trans- mission at this synapse. Local stimulation of the neostriatal slice evokes a field potential composed
Dual modulation of excitatory synaptic transmission by agonists at group I metabotropic glutamate receptors in the rat spinal dorsal horn.
Zhong, J; Gerber, G; Koji?, L; Randi?, M
The effects of group I metabotropic glutamate (mGlu) receptors on excitatory transmission in the rat dorsal horn, but mostly substantia gelatinosa, neurons were investigated using conventional intracellular recording in slices. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD), the group I mGlu receptor selective agonist (S)-3, 5-dihydroxyphenylglycine (DHPG), and the selective mGlu subtype 5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), all induce long-lasting depression of A primary afferent fibers-mediated monosynaptic excitatory postsynaptic potential (EPSP), and long-lasting potentiation of polysynaptic EPSP, and EPSP in cells receiving C-afferent fiber input. The DHPG potentiation of polysynaptic EPSP was partially or fully reversed by (S)-4-carboxyphenylglycine (S-4CPG), the mGlu subtype 1 preferring antagonist. 2-Methyl-6-(phenylethynyl)-pyridine, the potent and selective mGlu subtype 5 antagonist, partially reversed the CHPG potentiation of polysynaptic EPSP. The effects of DHPG on monosynaptic and polysynaptic EPSPs were reduced, or abolished, by the N-methyl-D-aspartate (NMDA) receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5). A clear and pronounced facilitation of the expression of DHPG- and CHPG-induced enhancement of polysynaptic EPSP, and EPSP evoked at C-fiber strength, was seen in the absence of gamma-aminobutyric acid subtype A receptor- and glycine-mediated synaptic inhibition. Besides dual modulation of excitatory synaptic transmission, DHPG induces depression of inhibitory postsynaptic potentials evoked by primary afferent stimulation in dorsal horn neurons. In addition, group I mGlu receptor agonists produced a direct persistent excitatory postsynaptic effect consisting of a slow membrane depolarization, an increase in input resistance, and an intense neuronal discharge. Cyclothiazide and (S)-4-CPG, the mGlu receptor subtype 1 preferring antagonists, significantly attenuated the DHPG-induced depolarization. These results demonstrate that the pharmacological activation of group I metabotropic glutamate receptors induces long-term depression (LTD) and long-term potentiation (LTP) of synaptic transmission in the spinal dorsal horn. These types of long-term synaptic plasticity may play a functional role in the generation of post-injury hypersensitivity (LTP) or antinociception (LTD). PMID:11134626
Biphasic cholinergic synaptic transmission controls action potential activity in thalamic reticular nucleus neurons
Sun, Yan-Gang; Pita-Almenar, Juan D.; Wu, Chia-Shan; Renger, John J.; Uebele, Victor N.; Lu, Hui-Chen; Beierlein, Michael
Cholinergic neurons in the basal forebrain and the brain stem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic ?4?2 nicotinic (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits. PMID:23365242
Transgenic rescue of SNAP-25 restores dopamine-modulated synaptic transmission in the coloboma mutant.
Steffensen, S C; Henriksen, S J; Wilson, M C
Many of the molecular components constituting the exocytotic machinery responsible for neurotransmitter release have been identified, yet the precise role played by these proteins in synaptic transmission, and their impact on neural function, has not been resolved. The mouse mutation coloboma is a contiguous gene defect that leads to electrophysiological and behavioral deficits and includes the gene-encoding SNAP-25, an integral component of the synaptic vesicle-docking/fusion core complex. The involvement of SNAP-25 in the hyperactive behavior of coloboma mice, which can be ameliorated by the indirect dopaminergic agonist, amphetamine, has been demonstrated by genetic rescue using a SNAP-25 transgene. Coloboma mice also exhibit increased recurrent inhibition, reduced theta rhythm by tail-pinch and reduced long-term potentiation in the hippocampal dentate gyrus that, as the hyperkinesis seen in these mutants suggests, may reflect impaired monoaminergic modulation. We sought to identify neurophysiological correlates of the rescued hyperactivity within hippocampal synaptic circuitry of SNAP-25 transgenic coloboma mutant mice. In contrast to the differences between coloboma and wild-type mice, there was no significant difference in the duration or amplitude of theta rhythmic activity (4-6 Hz) induced by tail-pinch (10 s), afferent-evoked field potentials, or paired-pulse responses recorded in the dentate gyrus of SNAP-25 transgenic coloboma and wild-type mice. Amphetamine (3.0 mg/kg, i.p.) produced disinhibition of dentate paired-pulse responses in both SNAP-25 transgenic and wild-type mice but increased inhibition in non-transgenic coloboma mice. These findings support the hypothesis that alteration of monoaminergic neurotransmission, which can be reversed by the indirect agonist, amphetamine, is particularly sensitive to alterations in the expression of SNAP-25. PMID:10575087
[My research life: from synaptic transmission to behavior].
Kuromi, Hiroshi
I have studied signal transmission at synapses and the effects of drugs on it at the molecular and cellular levels. Specific areas of research interest are outlined here. 1) Electrophysiological experiments in cats and rabbits suggested that a new type of analgesic, the phenothiazine derivative levomepromazine, exerts analgesic effects by depressing emotional responses accompanying the sensation of pain. 2) It was hypothesized that motoneurons had long-term effects on muscle cell membrane properties, in addition to controlling moment-to-moment activities. The substance to recover the post-denervation changes in muscle properties in culture was partially purified from mouse nerve extract, which suggested that trophic influences were exerted by substances released from motoneurons. 3) Muscles innervated by adrenergic fibers had sites responsive to acetylcholine as well as to adrenaline in early life in chicks, but only the adrenaline-responsive sites remained during development. Acetylcholine receptor clusters on Xenopus muscles were concentrated at the cholinergic neuromuscular junctions by the movement of receptors from outside the junctions during development. The passive diffusion-trap mechanism explained the accumulation of synaptic receptors at synapses. 4) We found two endocytic pathways and pools of synaptic vesicles contributing to low- and high-frequency synaptic transmission at Drosophila nerve terminals. We then identified two Ca2+ channels designated for the low- and high-frequency endocytosis of synaptic vesicles, straightjacket Ca2+ channels in the active zone and La3+-sensitive Ca2+ channels in the inactive zone at the terminals, respectively. Recently, Drosophila melanogaster has been used as a model for studying the social brain, and the heat avoidance response of the flies was found to be socially enhanced. Future studies are expected to reveal mechanisms underlying social brain functions at the gene level. PMID:25088317
Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
Fukata, Yuko; Lovero, Kathryn L; Iwanaga, Tsuyoshi; Watanabe, Atsushi; Yokoi, Norihiko; Tabuchi, Katsuhiko; Shigemoto, Ryuichi; Nicoll, Roger A; Fukata, Masaki
Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1(+/-)) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy. PMID:20133599
Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy
Fukata, Yuko; Lovero, Kathryn L.; Iwanaga, Tsuyoshi; Watanabe, Atsushi; Yokoi, Norihiko; Tabuchi, Katsuhiko; Shigemoto, Ryuichi; Nicoll, Roger A.; Fukata, Masaki
Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1?/?) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1+/?) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor–mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy. PMID:20133599
Contribution of NR2B Subunits to Synaptic Transmission in Amygdaloid Interneurons
Csaba Szinyei; Oliver Stork; Hans-Christian Pape
Synaptic responses of interneurons in the rat lateral amygdala (LA) to electrical microstimulation of putative cortical and thalamic afferents were studied in slice preparations in situ. The EPSPs at both thalamic and cortical inputs were composed of two major compo- nents that were sensitive to 6,7-dinitroxaline-2,3-dione and DL-2-amino-5-phosphonovaleric acid (APV), indicating mediation through AMPA and NMDA receptors. NMDA receptor activation
Interactions of Human Autoantibodies with Hippocampal GABAergic Synaptic Transmission – Analyzing Antibody-Induced Effects ex vivo
Haselmann, Holger; Röpke, Luise; Werner, Christian; Kunze, Albrecht; Geis, Christian
Autoantibodies (aAB) to the presynaptic located enzyme glutamate decarboxylase 65 (GAD65) are a characteristic attribute for a variety of autoimmune diseases of the central nervous system including subtypes of limbic encephalitis, stiff person-syndrome, cerebellar ataxia, and Batten's disease. Clinical signs of hyperexcitability and improvement of disease symptoms upon immunotherapy in some of these disorders suggest a possible pathogenic role of associated aAB. Recent experimental studies report inconsistent results regarding a direct pathogenic influence of anti-GAD65 aAB affecting inhibitory synaptic transmission in central GABAergic pathways. We here provide a method for direct evaluation of aAB-induced pathomechanisms in the intact hippocampal network. Purified patient IgG fractions containing aAB to GAD65 together with fixable lipophilic styryl dyes (FMdyes) are stereotactically injected into the hilus and the dentate gyrus in anesthetized mice. Twenty-four hours after intrahippocampal injection, acute hippocampal slices are prepared and transferred to a patch-clamp recording setup equipped with a fluorescence light source. Intraneural incorporated FMdyes show correct injection site for patch-clamp recording. Whole-cell patch-clamp recordings are performed from granule cells in the dentate gyrus and extracellular stimulation is applied in the border area of the dentate gyrus-hilus region to stimulate GABAergic afferents arising from parvalbumin positive basket cells. GABA-A receptor mediated inhibitory postsynaptic currents (IPSC) and miniature IPSC are recorded after blocking glutamatergic transmission. This approach allows investigation of potential aAB-induced effects on GABA-A receptor signaling ex vivo in an intact neuronal network. This offers several advantages compared to experimental procedures used in previous studies by in?vitro AB preincubation of primary neurons or slice preparations. Furthermore, this method requires only small amounts of patient material that are often limited in rare diseases. PMID:26124746
Selective role for trkB neurotrophin receptors in rapid modulation of hippocampal synaptic transmission
Eric S. Levine; Cheryl F. Dreyfus; Ira B. Black; Mark R. Plummer
Neurotrophins regulate neuronal survival and phenotypic differentiation. Recent evidence also suggests a role in the modulation of synaptic activity. Using neuronal cell cultures from embryonic hippocampus, we previously found that application of brain-derived neurotrophic factor rapidly enhanced synaptic transmission. We now report that application of neurotrophin-4, another ligand for the trkB neurotrophin receptor, was equally effective in enhancing synaptic currents.
Short communication Short-term depression of synaptic transmission from rat lateral
Zhou, Yi-Feng
Short communication Short-term depression of synaptic transmission from rat lateral geniculate Laboratory, School of Life Sciences, University of Science and Technology of China, 96 Jingzhai Road, Hefei-term synaptic plasticity, paired-pulse depression (PPD) and frequency depression, were prominent in the adult
Altered Electrical Properties in Drosophila Neurons Developing without Synaptic Transmission
Richard A. Baines; Jay P. Uhler; Annemarie Thompson; Sean T. Sweeney; Michael Bate
We examine the role of synaptic activity in the development of identified Drosophila embryonic motorneurons. Synaptic activ- ity was blocked by both pan-neuronal expression of tetanus toxin light chain (TeTxLC) and by reduction of acetylcholine (ACh) using a temperature-sensitive allele of choline acetyl- transferase (Cha ts2). In the absence of synaptic activity, aCC and RP2 motorneurons develop with an apparently
Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats
Petruska, Jeffrey C.; Kitay, Brandon; Boyce, Vanessa S.; Kaspar, Brian; Pearse, Damien; Gage, Fred H.; Mendell, Lorne M.
We examined whether elevating levels of neurotrophin-3 (NT-3) in the spinal cord and dorsal root ganglion (DRG) would alter connections made by muscle spindle afferent fibers on motoneurons. Adeno-associated virus (AAV) serotypes AAV1, AAV2 and AAV5, selected for their tropism profile, were engineered with the NT-3 gene and administered to the medial gastrocnemius muscle in adult rats. ELISA studies in muscle, DRG and spinal cord revealed that NT-3 concentration in all tissues peaked about 3 months after a single viral injection; after 6 months NT-3 concentration returned to normal values. Intracellular recording in triceps surae motoneurons revealed complex electrophysiological changes. Moderate elevation in cord NT-3 resulted in diminished segmental excitatory postsynaptic potential (EPSP) amplitude, perhaps as a result of the observed decrease in motoneuron input resistance. With further elevation in NT-3 expression, the decline in EPSP amplitude was reversed indicating that NT-3 at higher concentration could increase EPSP amplitude. No correlation was observed between EPSP amplitude and NT-3 concentration in the DRG. Treatment with control viruses could elevate NT-3 levels minimally resulting in measurable electrophysiological effects, perhaps as a result of inflammation associated with injection. EPSPs elicited by stimulation of the ventrolateral funiculus underwent a consistent decline in amplitude independent of NT-3 level. These novel correlations between modified NT-3 expression and single-cell electrophysiological parameters indicate that intramuscular administration of AAV(NT-3) can exert long lasting effects on synaptic transmission to motoneurons. This approach to neurotrophin delivery could be useful in modifying spinal function after injury. PMID:20849530
Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse
Sikand, Parul; Premkumar, Louis S
Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiology of chronic pain conditions. In this study, we have examined the modulation of TRPV1-mediated enhancement of excitatory synaptic transmission in response to PKC activation. Miniature excitatory postsynaptic currents (mEPSCs) from embryonic rat DRG–DH neuronal cocultures were recorded by patch clamping DH neurons. Capsaicin potently increased the frequency but not the amplitude of mEPSCs in a calcium-dependent manner, suggesting TRPV1-mediated glutamate release from presynaptic terminals of sensory neurons. Continued or repeated applications of capsaicin reduced the frequency of mEPSCs over time. The PKC activator phorbol 12,13-dibutyrate (PDBu) alone increased mEPSC events to a certain extent in a reversible manner but capsaicin further synergistically enhanced the frequency of mEPSCs. The PKC inhibitor bisindolylmaleimide (BIM) abolished PDBu-mediated potentiation of TRPV1-dependent increases in mEPSC frequency, suggesting modulation of TRPV1 by PKC-induced phosphorylation. In addition, at normal body temperatures (?37°C) PKC-mediated enhancement of mEPSC frequency is significantly decreased by a specific TRPV1 antagonist, suggesting a physiological role of TRPV1 at the central terminals. Furthermore, bradykinin (BK) significantly potentiated TRPV1-modulated synaptic responses by activating the PLC-PKC pathway. Our results indicate that TRPV1 activation can modulate excitatory synaptic transmission at the first sensory synapse and its effects can further be augmented by activation of PKC. Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions. Selective targeting of TRPV1 expressed on the central terminals of sensory neurons may serve as a strategy to alleviate chronic intractable pain conditions. PMID:17363391
The interplay between inflammatory cytokines and the endocannabinoid system in the regulation of synaptic transmission.
Rossi, Silvia; Motta, Caterina; Musella, Alessandra; Centonze, Diego
Excessive glutamate-mediated synaptic transmission and secondary excitotoxicity have been proposed as key determinants of neurodegeneration in many neurological diseases. Soluble mediators of inflammation have recently gained attention owing to their ability to enhance glutamate transmission and affect synaptic sensitivity to neurotransmitters. In the complex crosstalk between soluble immunoactive molecules and synapses, the endocannabinoid system (ECS) plays a central role, exerting an indirect neuroprotective action by inhibiting cytokine-dependent synaptic alterations, and a direct neuroprotective effect by limiting glutamate transmission and excitotoxic damage. On the other hand, the endocannabinoid (eCB)-mediated control of synaptic transmission is altered by proinflammatory cytokines with consequent effects in central nervous system (CNS) disorders. In this review, we summarize the interactions, at the pre- and postsynaptic level, between major inflammatory cytokines and the ECS. In addition, the behavioral and clinical consequences of the modulation of synaptic transmission during neuroinflammation are discussed. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID:25268960
Achieving High-Frequency Optical Control of Synaptic Transmission
Jackman, Skyler L.; Beneduce, Brandon M.; Drew, Iain R.
The optogenetic tool channelrhodopsin-2 (ChR2) is widely used to excite neurons to study neural circuits. Previous optogenetic studies of synapses suggest that light-evoked synaptic responses often exhibit artificial synaptic depression, which has been attributed to either the inability of ChR2 to reliably fire presynaptic axons or to ChR2 elevating the probability of release by depolarizing presynaptic boutons. Here, we compare light-evoked and electrically evoked synaptic responses for high-frequency stimulation at three synapses in the mouse brain. At synapses from Purkinje cells to deep cerebellar nuclei neurons (PC?DCN), light- and electrically evoked synaptic currents were remarkably similar for ChR2 expressed transgenically or with adeno-associated virus (AAV) expression vectors. For hippocampal CA3?CA1 synapses, AAV expression vectors of serotype 1, 5, and 8 led to light-evoked synaptic currents that depressed much more than electrically evoked currents, even though ChR2 could fire axons reliably at up to 50 Hz. The disparity between optical and electrical stimulation was eliminated when ChR2 was expressed transgenically or with AAV9. For cerebellar granule cell to stellate cell (grc?SC) synapses, AAV1 also led to artificial synaptic depression and AAV9 provided superior performance. Artificial synaptic depression also occurred when stimulating over presynaptic boutons, rather than axons, at CA3?CA1 synapses, but not at PC?DCN synapses. These findings indicate that ChR2 expression methods and light stimulation techniques influence synaptic responses in a neuron-specific manner. They also identify pitfalls associated with using ChR2 to study synapses and suggest an approach that allows optogenetics to be applied in a manner that helps to avoid potential complications. PMID:24872574
Synaptic Reorganization in the Substantia Gelatinosa After Peripheral Nerve Neuroma Formation: Aberrant Innervation of Lamina II Neurons by Ab Afferents
Ikuhide Koham; Kuniko Ishikawa; Jeffery D. Kocsis
Intracellular recording and extracellular field potential (FP) re- cordings were obtained from spinal cord dorsal horn neurons (laminae I-IV) in a rat transverse slice preparation with attached dorsal roots. To study changes in synaptic inputs after neuroma formation, the sciatic nerve was sectioned and ligated 3 weeks before in vitro electrophysiological analysis. Horseradish per- oxidase labeling of dorsal root axons
Distinct modulatory effects of 5-HT on excitatory synaptic transmissions in the nucleus tractus solitarius of the rat.
Takenaka, Ryosuke; Ohi, Yoshiaki; Haji, Akira
The second-order relay neurons in the nucleus tractus solitarius (NTS) receive numerous peripheral afferent inputs mainly from the vagus nerve. Their activity is modified by several neuromodulators and hence autonomic responses are properly regulated. Serotonin (5-HT) is an important candidate for such neuromodulators, since serotonergic inputs and distribution of 5-HT receptors are provided in the NTS. However, its mechanism of action remains unclear. To evaluate the serotonergic modulation of synaptic transmission, we examined the effects of 5-HT (1.0-10.0 ?M) on the solitary tract-evoked excitatory postsynaptic currents (eEPSCs) and spontaneously occurring EPSCs (sEPSCs) in the preselected second-order neurons of the rat NTS. 5-HT concentration-dependently decreased the amplitude of eEPSCs, which was accompanied by an increase in paired-pulse ratio. The inhibitory effect of 5-HT was mimicked by ?-methylserotonin and blocked by ketanserin. 5-HT had no effect on the inward current induced in the NTS neurons by topically applied ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). On the other hand, 5-HT increased the frequency of sEPCSs without effect on their amplitude. This excitatory effect of 5-HT was mimicked by 2-methylserotonin and antagonized by ondansetron. The results suggest a dual modulation of the excitatory synaptic transmission by 5-HT in the NTS; presynaptic inhibition of the peripheral inputs synapsing to the relay neurons via 5-HT(2) receptors and presynaptic excitation of inputs from the intrinsic local network via 5-HT(3) receptors. These effects of 5-HT may provide important means of optimizing the autonomic responses mediated by the NTS network. PMID:21968141
Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum
Dobson, Katharine L.; Bellamy, Tomas C.
In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic "ectopic" sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16?Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia. PMID:26171253
GABAAR-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus tadpoles in vivo
Shen, Wanhua; Da Silva, Jorge Santos; He, Haiyan; Cline, Hollis T.
The emergence of dendritic arbor structure in vivo depends on synaptic inputs. We tested whether inhibitory GABAergic synaptic transmission regulates Xenopus optic tectal cell dendritic arbor development in vivo by expressing a peptide corresponding to an intracellular loop (ICL) of the ?2 subunit of GABAAR which is required to anchor GABAA receptors to the postsynaptic scaffold. GFP-tagged ICL (EGFP-ICL) was distributed in a punctate pattern at putative inhibitory synapses, identified by VGAT-immunoreactive puncta. ICL expression completely blocked GABAAR - mediated transmission in 36% of transfected neurons and significantly reduced GABAAR - mediated synaptic currents relative to AMPAR-mediated synaptic currents in the remaining transfected neurons without altering release probability or neuronal excitability. Further analysis of ICL-expressing neurons with residual GABAAR- mediated inputs showed that the capacity of benzodiazepine to enhance GABAergic synaptic responses was reduced in ICL-expressing neurons, indicating that they were likely depleted of ?2 subunit-containing GABAAR. Neurons expressing a mutant form of ICL were comparable to controls. In vivo time-lapse images showed that ICL-expressing neurons have more sparsely branched dendritic arbors which expand over larger neuropil areas than EGFP-expressing control neurons. Analysis of branch dynamics indicated that ICL expression affected arbor growth by reducing rates of branch addition. Furthermore, we found that decreasing GABAergic synaptic transmission with ICL expression blocked visual experience dependent dendritic arbor structural plasticity. Our findings establish an essential role for inhibitory GABAergic synaptic transmission in the regulation of dendritic structural plasticity in Xenopus in vivo. PMID:19369572
Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism
Banerjee, Anwesha; García-Oscos, Francisco; Roychowdhury, Swagata; Galindo, Luis C.; Hall, Shawn; Kilgard, Michael P.; Atzori, Marco
The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical ?-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD. PMID:23228615
Nitric oxide: a novel link between synaptic and nonsynaptic transmission
János P. Kiss; E. Sylvester Vizi
Accumulating evidence indicates that nitric oxide (NO) inhibits the function of monoamine transporters. Because the production of NO by neuronal NO synthase (nNOS) is closely related to the activation of NMDA receptors, the level of NO around nNOS-containing synapses reflects the activity of glutamate-mediated neurotransmission. Glutamate participates mainly in synaptic interactions, but with the help of NO, the strength of
Chondroitin Sulfate Induces Depression of Synaptic Transmission and Modulation of Neuronal Plasticity in Rat Hippocampal Slices
Albińana, Elisa; Gutierrez-Luengo, Javier; Hernández-Juarez, Natalia; Baraibar, Andrés M.; Montell, Eulalia; Vergés, Josep; García, Antonio G.; Hernández-Guijo, Jesus M.
It is currently known that in CNS the extracellular matrix is involved in synaptic stabilization and limitation of synaptic plasticity. However, it has been reported that the treatment with chondroitinase following injury allows the formation of new synapses and increased plasticity and functional recovery. So, we hypothesize that some components of extracellular matrix may modulate synaptic transmission. To test this hypothesis we evaluated the effects of chondroitin sulphate (CS) on excitatory synaptic transmission, cellular excitability, and neuronal plasticity using extracellular recordings in the CA1 area of rat hippocampal slices. CS caused a reversible depression of evoked field excitatory postsynaptic potentials in a concentration-dependent manner. CS also reduced the population spike amplitude evoked after orthodromic stimulation but not when the population spikes were antidromically evoked; in this last case a potentiation was observed. CS also enhanced paired-pulse facilitation and long-term potentiation. Our study provides evidence that CS, a major component of the brain perineuronal net and extracellular matrix, has a function beyond the structural one, namely, the modulation of synaptic transmission and neuronal plasticity in the hippocampus.
Purines released from astrocytes inhibit excitatory synaptic transmission in the ventral horn of the spinal cord
Carlsen, Eva Meier; Perrier, Jean-François
Spinal neuronal networks are essential for motor function. They are involved in the integration of sensory inputs and the generation of rhythmic motor outputs. They continuously adapt their activity to the internal state of the organism and to the environment. This plasticity can be provided by different neuromodulators. These substances are usually thought of being released by dedicated neurons. However, in other networks from the central nervous system synaptic transmission is also modulated by transmitters released from astrocytes. The star-shaped glial cell responds to neurotransmitters by releasing gliotransmitters, which in turn modulate synaptic transmission. Here we investigated if astrocytes present in the ventral horn of the spinal cord modulate synaptic transmission. We evoked synaptic inputs in ventral horn neurons recorded in a slice preparation from the spinal cord of neonatal mice. Neurons responded to electrical stimulation by monosynaptic EPSCs (excitatory monosynaptic postsynaptic currents). We used mice expressing the enhanced green fluorescent protein under the promoter of the glial fibrillary acidic protein to identify astrocytes. Chelating calcium with BAPTA in a single neighboring astrocyte increased the amplitude of synaptic currents. In contrast, when we selectively stimulated astrocytes by activating PAR-1 receptors with the peptide TFLLR, the amplitude of EPSCs evoked by a paired stimulation protocol was reduced. The paired-pulse ratio was increased, suggesting an inhibition occurring at the presynaptic side of synapses. In the presence of blockers for extracellular ectonucleotidases, TFLLR did not induce presynaptic inhibition. Puffing adenosine reproduced the effect of TFLLR and blocking adenosine A1 receptors with 8-Cyclopentyl-1,3-dipropylxanthine prevented it. Altogether our results show that ventral horn astrocytes are responsible for a tonic and a phasic inhibition of excitatory synaptic transmission by releasing ATP, which gets converted into adenosine that binds to inhibitory presynaptic A1 receptors. PMID:24926236
Epilepsy-Related Ligand\\/Receptor Complex LGI1 and ADAM22 Regulate Synaptic Transmission
Yuko Fukata; Hillel Adesnik; Tsuyoshi Iwanaga; David S. Bredt; Roger A. Nicoll; Masaki Fukata
Abnormally synchronized synaptic transmission in the brain causes epilepsy. Most inherited forms of epilepsy result from mutations in ion channels. However, one form of epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF), is characterized by mutations in a secreted neuronal protein, LGI1. We show that ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor
Thermal Preconditioning and Heat-Shock Protein 72 Preserve Synaptic Transmission during Thermal Stress
Robertson, Meldrum
Thermal Preconditioning and Heat-Shock Protein 72 Preserve Synaptic Transmission during Thermal, exposing the mammalian CNS to nonle- thal heat stress (i.e., thermal preconditioning) increases levels that generates respiratory rhythm (the pre- Bo¨ tzinger complex), we show that thermal preconditioning has
MATERNAL HYPOTHYROXINEMIA LEADS TO PERSISTENT DEFICITS IN HIPPOCAMPAL SYNAPTIC TRANSMISSION AND LEARNING IN RAT OFFSPRING. M.E. Gilbert1 and Li Sui2, Neurotoxicology Division, 1US EPA and 2National Research Council, Research Triangle Pk, NC 27711. While severe hypothyroidis...
Long-Lasting Neurotrophin-Induced Enhancement of Synaptic Transmission in the Adult Hippocampus
Hyejin Kang; Erin M. Schuman
The neurotrophins are signaling factors important for the differentiation and survival of distinct neuronal populations during development. To test whether the neurotrophins also function in the mature nervous system, the effects of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophic factor 3 (NT-3) on the strength of synaptic transmission in hippocampal slices were determined. Application of BDNF or
Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices
F. Berger; A. Hensel; K. Nieber
Saffron, the dried stigmata of Crocus sativus L., is used in traditional medicine for a wide range of indications including cramps, asthma, and depression. To investigate the influence of hydro-ethanolic saffron extract (CSE) and trans-crocetin on synaptic transmission, postsynaptic potentials (PSPs) were elicited by focal electrical stimulation and recorded using intracellular placed microelectrodes in pyramidal cells from rat cingulate cortex.
Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
Karayannis, T; Au, E; Patel, J C; Kruglikov, I; Markx, S; Delorme, R; Héron, D; Salomon, D; Glessner, J; Restituito, S; Gordon, A; Rodriguez-Murillo, L; Roy, N C; Gogos, J A; Rudy, B; Rice, M E; Karayiorgou, M; Hakonarson, H; Keren, B; Huguet, G; Bourgeron, T; Hoeffer, C; Tsien, R W; Peles, E; Fishell, G
Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (?-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders. PMID:24870235
Enhanced synaptic transmission at the squid giant synapse by artificial seawater based on physically modified saline
Choi, Soonwook; Yu, Eunah; Rabello, Guilherme; Merlo, Suelen; Zemmar, Ajmal; Walton, Kerry D.; Moreno, Herman; Moreira, Jorge E.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.
Superfusion of the squid giant synapse with artificial seawater (ASW) based on isotonic saline containing oxygen nanobubbles (RNS60 ASW) generates an enhancement of synaptic transmission. This was determined by examining the postsynaptic response to single and repetitive presynaptic spike activation, spontaneous transmitter release, and presynaptic voltage clamp studies. In the presence of RNS60 ASW single presynaptic stimulation elicited larger postsynaptic potentials (PSP) and more robust recovery from high frequency stimulation than in control ASW. Analysis of postsynaptic noise revealed an increase in spontaneous transmitter release with modified noise kinetics in RNS60 ASW. Presynaptic voltage clamp demonstrated an increased EPSP, without an increase in presynaptic ICa++ amplitude during RNS60 ASW superfusion. Synaptic release enhancement reached stable maxima within 5–10 min of RNS60 ASW superfusion and was maintained for the entire recording time, up to 1 h. Electronmicroscopic morphometry indicated a decrease in synaptic vesicle density and the number at active zones with an increase in the number of clathrin-coated vesicles (CCV) and large endosome-like vesicles near junctional sites. Block of mitochondrial ATP synthesis by presynaptic injection of oligomycin reduced spontaneous release and prevented the synaptic noise increase seen in RNS60 ASW. After ATP block the number of vesicles at the active zone and CCV was reduced, with an increase in large vesicles. The possibility that RNS60 ASW acts by increasing mitochondrial ATP synthesis was tested by direct determination of ATP levels in both presynaptic and postsynaptic structures. This was implemented using luciferin/luciferase photon emission, which demonstrated a marked increase in ATP synthesis following RNS60 administration. It is concluded that RNS60 positively modulates synaptic transmission by up-regulating ATP synthesis, thus leading to synaptic transmission enhancement. PMID:24575037
Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice.
Brown, Jon T; Richardson, Jill C; Collingridge, Graham L; Randall, Andrew D; Davies, Ceri H
Synaptic transmission was studied in hippocampal slices from aged (12-14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3-CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 microM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4+/-0.6 s; TAS10, 6.9+/-1.7 s). To study gamma-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 microM) and D-AP5 (50 microM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing. PMID:15390159
Effects of clozapine and N-desmethylclozapine on synaptic transmission at hippocampal inhibitory and excitatory synapses.
Ohno-Shosaku, Takako; Sugawara, Yuto; Muranishi, Chiho; Nagasawa, Keisuke; Kubono, Kozue; Aoki, Nami; Taguchi, Mitsuki; Echigo, Ryousuke; Sugimoto, Naotoshi; Kikuchi, Yui; Watanabe, Ryoko; Yoneda, Mitsugu
Clozapine is the first atypical antipsychotic, and improves positive and negative symptoms of many patients with schizophrenia resistant to treatment with other antipsychotic agents. Clozapine induces minimal extrapyramidal side effects, but is more often associated with seizures. A large number of studies have been conducted to elucidate pharmacological profiles of clozapine and its major active metabolite, N-desmethylclozapine (NDMC). However, there are only a limited number of electrophysiological studies examining their effects on synaptic transmission. In this study, we examined effects of clozapine and NDMC on synaptic transmission by measuring inhibitory and excitatory postsynaptic currents in rat cultured hippocampal neurons. We found that clozapine and NDMC have qualitatively similar actions. They depressed the inhibitory transmission at 1-30 ?M, and the excitatory transmission at 30 ?M, the former being much more sensitive. The depression of IPSCs by 30 ?M of these drugs was associated with an increase in the paired-pulse ratio. The GABA-induced currents were suppressed by these drugs, but less sensitive than IPSCs. The AMPA-induced currents were slightly potentiated by these drugs at 30 ?M. At 30 ?M, clozapine and NDMC slightly suppressed Ca(2+) and Na(+) channels. These results strongly suggest that clozapine and NMDC depress the inhibitory synaptic transmission mainly by antagonizing postsynaptic GABA(A) receptors, but at higher concentrations additionally by acting on presynaptic site, possibly in part through inhibition of presynaptic Ca(2+) and Na(+) channels. Preferential depression of inhibitory synaptic transmission by clozapine and NDMC might contribute to therapeutic actions and/or side-effects of clozapine. PMID:21945084
Kismet Positively Regulates Glutamate Receptor Localization and Synaptic Transmission at the Drosophila Neuromuscular Junction
Ghosh, Rupa; Vegesna, Srikar; Safi, Ramia; Bao, Hong; Zhang, Bing; Marenda, Daniel R.; Liebl, Faith L. W.
The Drosophila neuromuscular junction (NMJ) is a glutamatergic synapse that is structurally and functionally similar to mammalian glutamatergic synapses. These synapses can, as a result of changes in activity, alter the strength of their connections via processes that require chromatin remodeling and changes in gene expression. The chromodomain helicase DNA binding (CHD) protein, Kismet (Kis), is expressed in both motor neuron nuclei and postsynaptic muscle nuclei of the Drosophila larvae. Here, we show that Kis is important for motor neuron synaptic morphology, the localization and clustering of postsynaptic glutamate receptors, larval motor behavior, and synaptic transmission. Our data suggest that Kis is part of the machinery that modulates the development and function of the NMJ. Kis is the homolog to human CHD7, which is mutated in CHARGE syndrome. Thus, our data suggest novel avenues of investigation for synaptic defects associated with CHARGE syndrome. PMID:25412171
Variance-mean analysis: a simple and reliable approach for investigating synaptic transmission and modulation.
Clements, John D
The mechanisms underlying synaptic plasticity can be investigated by analyzing synaptic amplitude fluctuations before and after a synaptic modulation. However, many older fluctuation analysis techniques rely on models of synaptic transmission that incorporate unrealistic simplifying assumptions or have too many free parameters. As a result, these techniques have sometimes produced counterintuitive or contradictory results. In contrast, the variance-mean (V-M) technique requires fewer assumptions and is more robust than previous approaches. It achieves these improvements by focusing on two key parameters of synaptic transmission, the average probability that a vesicle is released from a synaptic terminal following a presynaptic stimulus (Pav), and the average amplitude of the postsynaptic response to a vesicle of transmitter (Qav). To apply V-M analysis, a fluctuating postsynaptic current (PSC) is recorded at several different extracellular Ca2+ or Cd2+ concentrations. The variance of the PSC amplitude is plotted against the mean amplitude at each concentration, forming a parabola. The degree of parabolic curvature estimates Pav, and the limiting slope under low release conditions estimates Qav. The shape of the V-M parabola changes in characteristic ways following each of the three standard forms of synaptic modulation: a change in Qav (postsynaptic), a change in Pav (presynaptic), or a change in the number of terminals (N). The approach does not require specialized software, and can even be implemented as a purely graphical technique. V-M analysis has been used to investigate the site of expression of long-term potentiation and the mechanisms underlying paired-pulse depression. This report presents a detailed mathematical development of the technique, and explores the limiting conditions under which it can confidently be applied. V-M analysis requires fewer than 100 PSC amplitude measurements to accurately estimate Pav and Qav, and it can reliably identify whether a synaptic modulation occurs at a pre- or postsynaptic site. In contrast to other techniques, V-M analysis is largely insensitive to recording noise, nonuniform modulation and intrinsic variability of the unitary synaptic amplitude. PMID:14667541
First effects of rising amyloid-? in transgenic mouse brain: synaptic transmission and gene expression.
Cummings, Damian M; Liu, Wenfei; Portelius, Erik; Bayram, Sevinç; Yasvoina, Marina; Ho, Sui-Hin; Smits, Hélčne; Ali, Shabinah S; Steinberg, Rivka; Pegasiou, Chrysia-Maria; James, Owain T; Matarin, Mar; Richardson, Jill C; Zetterberg, Henrik; Blennow, Kaj; Hardy, John A; Salih, Dervis A; Edwards, Frances A
Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-?. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-? peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-? peptides in a mouse model of increasing amyloid-? ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-? peptides were above the limit of detection, including amyloid-?40, amyloid-?38 and amyloid-?42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-? levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-?40 rose by ?7-fold, but amyloid-?42 rose by 25-fold, increasing the amyloid-?42:amyloid-?40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-?) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-? levels and amyloid-?42:amyloid-?40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-?, the initial deposition of plaques does not occur until several months after the first amyloid-? becomes detectable but coincides with a rapid acceleration in the rise of amyloid-? levels and the amyloid-?42:amyloid-?40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease. PMID:25981962
Endogenous neurokinins facilitate synaptic transmission in guinea pig airway parasympathetic ganglia.
Canning, Brendan J; Reynolds, Sandra M; Anukwu, Linus U; Kajekar, Radhika; Myers, Allen C
Neurokinin-containing nerve fibers were localized to guinea pig airway parasympathetic ganglia in control tissues but not in tissues pretreated with capsaicin. The purpose of the present study was to determine whether neurokinins, released during axonal reflexes or after antidromic afferent nerve stimulation, modulate ganglionic synaptic neurotransmission. The neurokinin type 3 (NK(3)) receptor antagonists SB-223412 and SR-142801 inhibited vagally mediated cholinergic contractions of bronchi in vitro at stimulation voltages threshold for preganglionic nerve activation but had no effect on vagally mediated contractions evoked at optimal voltage or field stimulation-induced contractions. Intracellular recordings from the ganglia neurons revealed that capsaicin-sensitive nerve stimulation potentiated subsequent preganglionic nerve-evoked fast excitatory postsynaptic potentials. This effect was mimicked by the NK(3) receptor agonist senktide analog and blocked by SB-223412. In situ, senktide analog markedly increased baseline tracheal cholinergic tone, an effect that was reversed by atropine and prevented by vagotomy or SB-223412. Comparable effects of intravenous senktide analog on pulmonary insufflation pressure were observed. These data highlight the important integrative role played by parasympathetic ganglia and indicate that activation of NK(3) receptors in airway ganglia by endogenous neurokinins facilitates synaptic neurotransmission. PMID:12121843
Quantal behaviour of synaptic transmission can be statistically examined using the Fourier line spectrum of the histogram of synaptic potentials.
Rusakov, D A
A statistical approach to reveal the quantal behaviour of postsynaptic potentials (PSPs) is described. This includes: (1) obtaining the Fourier line spectrum (decomposition into harmonics) of the PSP histogram; and (2) testing the null hypothesis, 'the spectrum is that of white noise', using an ANOVA. The harmonic that rejects the hypothesis will indicate the regular peaks in the histogram, i.e., the quantal size of PSPs. The method was tested using published results of three experimental studies in central synapses and yielded the quantal sizes close to those derived from other methods. However, using three examples of published simulation studies (where the quantal model of synaptic transmission was known a priori), it was shown that the approach can estimate quantal sizes of PSPs more reliably than other methods. PMID:8309640
The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling.
Liu, D; Wei, N; Man, H-Y; Lu, Y; Zhu, L-Q; Wang, J-Z
The MT2 receptor is a principal type of G protein-coupled receptor that mainly mediates the effects of melatonin. Deficits of melatonin/MT2 signaling have been found in many neurological disorders, including Alzheimer's disease, the most common cause of dementia in the elderly, suggesting that preservation of the MT2 receptor may be beneficial to these neurological disorders. However, direct evidence linking the MT2 receptor to cognition-related synaptic plasticity remains to be established. Here, we report that the MT2 receptor, but not the MT1 receptor, is essential for axonogenesis both in vitro and in vivo. We find that axon formation is retarded in MT2 receptor knockout mice, MT2-shRNA electroporated brain slices or primary neurons treated with an MT2 receptor selective antagonist. Activation of the MT2 receptor promotes axonogenesis that is associated with an enhancement in excitatory synaptic transmission in central neurons. The signaling components downstream of the MT2 receptor consist of the Akt/GSK-3?/CRMP-2 cascade. The MT2 receptor C-terminal motif binds to Akt directly. Either inhibition of the MT2 receptor or disruption of MT2 receptor-Akt binding reduces axonogenesis and synaptic transmission. Our data suggest that the MT2 receptor activates Akt/GSK-3?/CRMP-2 signaling and is necessary and sufficient to mediate functional axonogenesis and synaptic formation in central neurons. PMID:25501601
Statistical models of synaptic transmission evaluated using the expectation-maximization algorithm.
Stricker, C; Redman, S
Amplitude fluctuations of evoked synaptic responses can be used to extract information on the probabilities of release at the active sites, and on the amplitudes of the synaptic responses generated by transmission at each active site. The parameters that describe this process must be obtained from an incomplete data set represented by the probability density of the evoked synaptic response. In this paper, the equations required to calculate these parameters using the Expectation-Maximization algorithm and the maximum likelihood criterion have been derived for a variety of statistical models of synaptic transmission. These models are ones where the probabilities associated with the different discrete amplitudes in the evoked responses are a) unconstrained, b) binomial, and c) compound binomial. The discrete amplitudes may be separated by equal (quantal) or unequal amounts, with or without quantal variance. Alternative models have been considered where the variance associated with the discrete amplitudes is sufficiently large such that no quantal amplitudes can be detected. These models involve the sum of a normal distribution (to represent failures) and a unimodal distribution (to represent the evoked responses). The implementation of the algorithm is described in each case, and its accuracy and convergence have been demonstrated. PMID:7948679
Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission.
Fukata, Yuko; Adesnik, Hillel; Iwanaga, Tsuyoshi; Bredt, David S; Nicoll, Roger A; Fukata, Masaki
Abnormally synchronized synaptic transmission in the brain causes epilepsy. Most inherited forms of epilepsy result from mutations in ion channels. However, one form of epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF), is characterized by mutations in a secreted neuronal protein, LGI1. We show that ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor for LGI1. LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 fails to bind to ADAM22. ADAM22 is anchored to the postsynaptic density by cytoskeletal scaffolds containing stargazin. These studies in rat brain indicate possible avenues for understanding human epilepsy. PMID:16990550
Synaptic and circuit mechanisms promoting broadband transmission of olfactory stimulus dynamics
Nagel, Katherine I.; Hong, Elizabeth J.; Wilson, Rachel I.
Sensory stimuli fluctuate on many timescales. However, short-term plasticity causes synapses to act as temporal filters, limiting the range of frequencies they can transmit. How synapses in vivo might transmit a range of frequencies in spite of short-term plasticity is poorly understood. The first synapse in the Drosophila olfactory system exhibits short-term depression, and yet can transmit broadband signals. Here we describe two mechanisms that broaden the frequency characteristics of this synapse. First, two distinct excitatory postsynaptic currents transmit signals on different timescales. Second, presynaptic inhibition dynamically updates synaptic properties to promote accurate transmission of signals across a wide range of frequencies. Inhibition is transient but grows slowly, and simulations show that these two features of inhibition promote broadband synaptic transmission. Dynamic inhibition is often thought to restrict the temporal patterns that a neuron responds to, but our results illustrate a different idea: inhibition can expand the bandwidth of neural coding. PMID:25485755
Synaptic and circuit mechanisms promoting broadband transmission of olfactory stimulus dynamics.
Nagel, Katherine I; Hong, Elizabeth J; Wilson, Rachel I
Sensory stimuli fluctuate on many timescales. However, short-term plasticity causes synapses to act as temporal filters, limiting the range of frequencies that they can transmit. How synapses in vivo might transmit a range of frequencies in spite of short-term plasticity is poorly understood. The first synapse in the Drosophila olfactory system exhibits short-term depression, but can transmit broadband signals. Here we describe two mechanisms that broaden the frequency characteristics of this synapse. First, two distinct excitatory postsynaptic currents transmit signals on different timescales. Second, presynaptic inhibition dynamically updates synaptic properties to promote accurate transmission of signals across a wide range of frequencies. Inhibition is transient, but grows slowly, and simulations reveal that these two features of inhibition promote broadband synaptic transmission. Dynamic inhibition is often thought to restrict the temporal patterns that a neuron responds to, but our results illustrate a different idea: inhibition can expand the bandwidth of neural coding. PMID:25485755
Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells
Rodion V. Kondratenko; Vladimir I. Derevyagin; Vladimir G. Skrebitsky
Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1?M) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating
Laser-evoked synaptic transmission in cultured hippocampal neurons channelrhodopsin-2 delivered by adeno-associated virus
Wang, Jennifer
We present a method for studying synaptic transmission in mass cultures of dissociated hippocampal neurons based on patch clamp recording combined with laser stimulation of neurons expressing channelrhodopsin-2 (ChR2). Our ...
Attenuation of inhibitory synaptic transmission by glial dysfunction in rat thalamus.
Yang, Sunggu; Cox, Charles L
The thalamus serves as the obligatory gateway to the neocortex for sensory processing, and also serves as a pathway for corticocortical communication. In addition, the reciprocal synaptic connectivity between the thalamic reticular nucleus (TRN) and adjacent thalamic relay nuclei generates rhythmic activities similar to that observed during different arousal states and certain neurological conditions such as absence epilepsy. Epileptiform activity can arise from a variety of neural mechanisms, but in addition glia are thought to have an important role in such activities as well. Glia serve a central role in glutamine synthesis, a precursor for glutamate or GABA in nerve terminals. While alterations in glutamine shuttling from glia to neurons can influence GABA and glutamate neurotransmission; the consequences of such action on synaptic transmission and subsequent network activities within thalamic circuits is less understood. We investigated the consequences of altering glutamine transport on inhibitory transmission and intrathalamic activities using the in vitro thalamic slice preparation. Disruption of the glutamine shuttling by the neuronal glutamine transporter (system A transporter) antagonist, ?-(methylamino)isobutyric acid (MeAIB), or the selective gliotoxic drug, fluorocitric acid (Fc) dramatically decreased intrathalamic rhythmic activities. At the single cell level, MeAIB and Fc significantly attenuated electrically evoked inhibitory postsynaptic currents (eIPSCs) in thalamic relay neurons; however, miniature IPSCs were unaffected. These data indicate that glutamate-glutamine shuttle is critical for sustaining thalamic synaptic transmission, and thereby alterations in this shuttle can influence intrathalamic rhythmic activities associated with absence epilepsy. PMID:21656574
Synaptic Transmission at the Cochlear Nucleus Endbulb Synapse during Age-Related Hearing Loss in Mice
Wang, Yong; Manis, Paul B.
Summary Age-related hearing loss (AHL) typically starts from high frequency regions of the cochlea and over time invades lower frequency regions. During this progressive hearing loss, sound-evoked activity in spiral ganglion cells is reduced. DBA mice have an early onset of AHL. In this study, we examined synaptic transmission at the endbulb of Held synapse between auditory nerve fibers and bushy cells in the anterior ventral cochlear nucleus (AVCN). Synaptic transmission in hearing-impaired high frequency areas of the AVCN was altered in old DBA mice. The spontaneous mEPSC frequency was greatly reduced (?60%), and mEPSCs were significantly slower (?115%) and smaller (?70%) in high frequency regions of old (average age 45d) DBA mice compared to tonotopically matched regions of young (average age 22d) DBA mice. Moreover, synaptic release probability was about 30% higher in high frequency regions of young DBA than that in old DBA mice. Auditory nerve-evoked EPSCs showed less rectification in old DBA mice, suggesting recruitment of GluR2 subunits into the AMPA receptor complex. No similar age-related changes in synaptic release or EPSCs were found in age matched, normal hearing young and old CBA mice. Taken together, our results suggest that auditory nerve activity plays a critical role in maintaining normal synaptic function at the endbulb of Held synapse after the onset of hearing. Auditory nerve activity regulates both presynaptic (release probability) and postsynaptic (receptor composition and kinetics) function at the endbulb synapse after the onset of hearing. PMID:15901757
RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission.
Cerpa, Waldo; Latorre-Esteves, Elena; Barria, Andres
Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development. PMID:25825749
Selective activation of microglia facilitates synaptic strength.
Clark, Anna K; Gruber-Schoffnegger, Doris; Drdla-Schutting, Ruth; Gerhold, Katharina J; Malcangio, Marzia; Sandkühler, Jürgen
Synaptic plasticity is thought to be initiated by neurons only, with the prevailing view assigning glial cells mere specify supportive functions for synaptic transmission and plasticity. We now demonstrate that glial cells can control synaptic strength independent of neuronal activity. Here we show that selective activation of microglia in the rat is sufficient to rapidly facilitate synaptic strength between primary afferent C-fibers and lamina I neurons, the first synaptic relay in the nociceptive pathway. Specifically, the activation of the CX3CR1 receptor by fractalkine induces the release of interleukin-1? from microglia, which modulates NMDA signaling in postsynaptic neurons, leading to the release of an eicosanoid messenger, which ultimately enhances presynaptic neurotransmitter release. In contrast to the conventional view, this form of plasticity does not require enhanced neuronal activity to trigger the events leading to synaptic facilitation. Augmentation of synaptic strength in nociceptive pathways represents a cellular model of pain amplification. The present data thus suggest that, under chronic pain states, CX3CR1-mediated activation of microglia drives the facilitation of excitatory synaptic transmission in the dorsal horn, which contributes to pain hypersensitivity in chronic pain states. PMID:25788673
Selective Activation of Microglia Facilitates Synaptic Strength
Clark, Anna K.; Gruber-Schoffnegger, Doris; Drdla-Schutting, Ruth; Gerhold, Katharina J.; Malcangio, Marzia
Synaptic plasticity is thought to be initiated by neurons only, with the prevailing view assigning glial cells mere specify supportive functions for synaptic transmission and plasticity. We now demonstrate that glial cells can control synaptic strength independent of neuronal activity. Here we show that selective activation of microglia in the rat is sufficient to rapidly facilitate synaptic strength between primary afferent C-fibers and lamina I neurons, the first synaptic relay in the nociceptive pathway. Specifically, the activation of the CX3CR1 receptor by fractalkine induces the release of interleukin-1? from microglia, which modulates NMDA signaling in postsynaptic neurons, leading to the release of an eicosanoid messenger, which ultimately enhances presynaptic neurotransmitter release. In contrast to the conventional view, this form of plasticity does not require enhanced neuronal activity to trigger the events leading to synaptic facilitation. Augmentation of synaptic strength in nociceptive pathways represents a cellular model of pain amplification. The present data thus suggest that, under chronic pain states, CX3CR1-mediated activation of microglia drives the facilitation of excitatory synaptic transmission in the dorsal horn, which contributes to pain hypersensitivity in chronic pain states. PMID:25788673
Intrinsic and Synaptic Long-Term Depression of NTS Relay of Nociceptin-Sensitive and Capsaicin-Sensitive Cardiopulmonary Afferents Hyperactivity
Feinberg-Zadek, Paula
The nucleus tractus solitarius (NTS) in the caudal medulla is a gateway for a variety of cardiopulmonary afferents important for homeostatic regulation and defense against airway and cardiovascular insults and is a key ...
Compartment-Specific Modulation of GABAergic Synaptic Transmission by TRPV1 Channels in the Dentate Gyrus
Hernández, Vivian M.; Rodenas-Ruano, Alma; Chan, C. Savio
The transient receptor potential TRPV1 or vanilloid receptor is a nonselective ligand-gated channel highly expressed in primary sensory neurons where it mediates nociception. TRPV1 is also expressed in the brain where its activation depresses excitatory synaptic transmission. Whether TRPV1 also regulates inhibitory synapses in the brain is unclear. Here, using a combination of pharmacology, electrophysiology, and an in vivo knockdown strategy, we report that TRPV1 activation by capsaicin or by the endocannabinoid anandamide depresses somatic, but not dendritic inhibitory transmission in both rat and mouse dentate gyrus. The effect on somatic inhibition was absent in TRPV1 knock-out mice and was also eliminated by two different TRPV1 shRNAs expressed in dentate granule cells, strongly supporting a functional role for TRPV1 in modulating GABAergic synaptic function. Moreover, TRPV1-mediated depression occurs independently of GABA release, requires postsynaptic Ca2+ rise and activation of calcineurin, and is likely due to clathrin-dependent internalization of GABA receptors. Altogether, these findings reveal a novel form of compartment-specific regulation whereby TRPV1 channels can modify synaptic function in the brain. PMID:25505315
Thrombin regulation of synaptic transmission and plasticity: implications for health and disease
Ben Shimon, Marina; Lenz, Maximilian; Ikenberg, Benno; Becker, Denise; Shavit Stein, Efrat; Chapman, Joab; Tanne, David; Pick, Chaim G.; Blatt, Ilan; Neufeld, Miri; Vlachos, Andreas; Maggio, Nicola
Thrombin, a serine protease involved in the blood coagulation cascade has been shown to affect neural function following blood-brain barrier breakdown. However, several lines of evidence exist that thrombin is also expressed in the brain under physiological conditions, suggesting an involvement of thrombin in the regulation of normal brain functions. Here, we review ours' as well as others' recent work on the role of thrombin in synaptic transmission and plasticity through direct or indirect activation of Protease-Activated Receptor-1 (PAR1). These studies propose a novel role of thrombin in synaptic plasticity, both in physiology as well as in neurological diseases associated with increased brain thrombin/PAR1 levels. PMID:25954157
Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses
Katz, Eleonora; Elgoyhen, Ana Belén
The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs) and outer hair cells (OHCs). In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC) system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2+ action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the ?9?10 nicotinic cholinergic receptor (nAChR) coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells. In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern. PMID:25520631
A TRPV channel in Drosophila motor neurons regulates presynaptic resting Ca2+ levels, synapse growth, and synaptic transmission.
Wong, Ching-On; Chen, Kuchuan; Lin, Yong Qi; Chao, Yufang; Duraine, Lita; Lu, Zhongmin; Yoon, Wan Hee; Sullivan, Jeremy M; Broadhead, Geoffrey T; Sumner, Charlotte J; Lloyd, Thomas E; Macleod, Gregory T; Bellen, Hugo J; Venkatachalam, Kartik
Presynaptic resting Ca(2+) influences synaptic vesicle (SV) release probability. Here, we report that a TRPV channel, Inactive (Iav), maintains presynaptic resting [Ca(2+)] by promoting Ca(2+) release from the endoplasmic reticulum in Drosophila motor neurons, and is required for both synapse development and neurotransmission. We find that Iav activates the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin, which is essential for presynaptic microtubule stabilization at the neuromuscular junction. Thus, loss of Iav induces destabilization of presynaptic microtubules, resulting in diminished synaptic growth. Interestingly, expression of human TRPV1 in Iav-deficient motor neurons rescues these defects. We also show that the absence of Iav causes lower SV release probability and diminished synaptic transmission, whereas Iav overexpression elevates these synaptic parameters. Together, our findings indicate that Iav acts as a key regulator of synaptic development and function by influencing presynaptic resting [Ca(2+)]. PMID:25451193
Hemichannel composition and electrical synaptic transmission: molecular diversity and its implications for electrical rectification
Palacios-Prado, Nicolás; Huetteroth, Wolf; Pereda, Alberto E.
Unapposed hemichannels (HCs) formed by hexamers of gap junction proteins are now known to be involved in various cellular processes under both physiological and pathological conditions. On the other hand, less is known regarding how differences in the molecular composition of HCs impact electrical synaptic transmission between neurons when they form intercellular heterotypic gap junctions (GJs). Here we review data indicating that molecular differences between apposed HCs at electrical synapses are generally associated with rectification of electrical transmission. Furthermore, this association has been observed at both innexin and connexin (Cx) based electrical synapses. We discuss the possible molecular mechanisms underlying electrical rectification, as well as the potential contribution of intracellular soluble factors to this phenomenon. We conclude that asymmetries in molecular composition and sensitivity to cellular factors of each contributing hemichannel can profoundly influence the transmission of electrical signals, endowing electrical synapses with more complex functional properties. PMID:25360082
Modulation of hippocampal synaptic transmission by the kynurenine pathway member xanthurenic acid and other VGLUT inhibitors.
Neale, S A; Copeland, C S; Uebele, V N; Thomson, F J; Salt, T E
Xanthurenic acid (XA), an endogenous kynurenine, is a known vesicular glutamate transport (VGLUT) inhibitor and has also been proposed as an mGlu2/3 receptor agonist. Changes in these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders; however, little is known of how XA affects synaptic transmission. We therefore investigated the effects of XA on synaptic transmission at two hippocampal glutamatergic pathways and evaluated the ability of XA to bind to mGlu2/3 receptors. Field excitatory postsynaptic potentials (fEPSPs) were recorded from either the dentate gyrus (DG) or CA1 region of mouse hippocampal slices in vitro. Addition of XA to the bathing medium (1-10?mM) resulted in a dose-related reduction of fEPSP amplitudes (up to 52% reduction) in both hippocampal regions. In the DG, the VGLUT inhibitors Congo Red and Rose Bengal, and the mGlu2/3 agonist LY354740, also reduced fEPSPs (up to 80% reduction). The mGlu2/3 antagonist LY341495 reversed the LY354740 effect, but not the XA effect. LY354740, but not XA, also reduced DG paired-pulse depression. XA had no effect on specific binding of 1?nM [(3)H]LY341495 to membranes with human mGlu2 receptors. We conclude that XA can modulate synaptic transmission via a mechanism that may involve VGLUT inhibition rather than activation of mGlu2/3 receptors. This could be important in the pathophysiology of nervous system disorders including schizophrenia and might represent a target for developing novel pharmacological therapies. PMID:23303071
Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS
Miwa, Hideki; Fukaya, Masahiro; Watabe, Ayako M; Watanabe, Masahiko; Manabe, Toshiya
The NMDA-type glutamate receptor is a heteromeric complex composed of the NR1 and at least one of the NR2 subunits. Switching from the NR2B to the NR2A subunit is thought to underlie functional alteration of the NMDA receptor during synaptic maturation, and it is generally believed that it results in preferential localization of NR2A subunits on the synaptic site and that of NR2B subunits on the extracellular site in the mature brain. It has also been proposed that activation of the NR2A and NR2B subunits results in long-term potentiation (LTP) and long-term depression (LTD), respectively. Furthermore, recent reports suggest that synaptic and extrasynaptic receptors may have distinct roles in synaptic plasticity as well as in gene expression associated with neuronal death. Here, we have investigated whether NR2B subunit-containing receptors are present and functional at mature synapses in the lateral nucleus of the amygdala (LA) and the CA1 region of the hippocampus, comparing their properties between the two brain regions. We have found, in contrast to the above hypotheses, that the NR2B subunit significantly contributes to synaptic transmission as well as LTP induction. Furthermore, its contribution is greater in the LA than in the CA1 region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit-containing NMDA receptors accumulate on the synaptic site and are responsible for the unique properties of synaptic function and plasticity in the amygdala. PMID:18372311
Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.
Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G
Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion. PMID:20382202
Stochastic resonance in Hodgkin-Huxley neuron induced by unreliable synaptic transmission.
Guo, Daqing; Li, Chunguang
We systematically investigate the stochastic dynamics of a single Hodgkin-Huxley neuron driven by stochastic excitatory and inhibitory input spikes via unreliable synapses in this paper. Based on the mean-filed theory, a novel intrinsic neuronal noise regulation mechanism stemming from unreliable synapses is presented. Our simulation results show that, under certain conditions, the stochastic resonance phenomenon is able to be induced by the unreliable synaptic transmission, which can be well explained by the theoretical prediction. To a certain degree, the results presented here provide insights into the functional roles of unreliable synapses in neural information processing. PMID:22687443
Synaptic transmission in the superior cervical ganglion of the cat after reinnervation by vagus fibres
Ceccarelli, B.; Clementi, F.; Mantegazza, P.
1. A vagus-sympathetic anastomosis was performed in the cat by connecting end to end the cranial trunk of the vagus to the cranial end of the cervical sympathetic trunk, both severed under the ganglia. 2. Forty to sixty days after the anastomosis, the ocular signs of sympathetic paralysis (such as myosis and prolapse of the nictitating membrane) which had developed shortly after the operation, had completely disappeared, thus suggesting the recovery of synaptic transmission in the ganglion. In case of plain preganglionic denervation after the same period the ocular signs of cervical sympathetic paralysis were still present. 3. Contraction of the nictitating membrane could be induced by electrical stimulation of both the vagus preanastomotic and the sympathetic postanastomotic—preganglionic trunks. Ganglionic blocking agents induced the blockade of the `new' ganglionic synaptic function, while nicotine and pilocarpine provoked a marked contraction of the nictitating membrane. 4. Electron microscopy showed that the preganglionic regeneration of vagus fibers resulted in the formation of new synapses, mainly of axodendritic type, identical to normal ganglionic synapses. Moreover, after cutting the preanastomotic trunk of the vagus, these new ganglionic presynaptic profiles degenerated, thus proving their vagal origin. 5. During restoration of the synaptic contacts readjustment of dendritic tips occurred. ImagesText-fig. 2Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13Fig. 16Fig. 17Fig. 14Fig. 15Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 7Fig. 8 PMID:4326851
D9Tetrahydrocannabinol Acts as a Partial Agonist to Modulate Glutamatergic Synaptic Transmission between Rat Hippocampal Neurons in Culture
D9-Tetrahydrocannabinol (D9-THC) is the principal psychoac- tive ingredient in marijuana. We examined the effects of D9- THC on glutamatergic synaptic transmission. Reducing the extracellular Mg11 concentration bathing rat hippocampal neu- rons in culture to 0.1 mM elicited a repetitive pattern of gluta- matergic synaptic activity that produced intracellular Ca11 concentration spikes that were measured by indo-1-based mi- crofluorimetry. D9-THC produced
Layer- and area-specificity of the adrenergic modulation of synaptic transmission in the rat neocortex.
Roychowdhury, Swagata; Zwierzchowski, Amy N; Garcia-Oscos, Francisco; Olguin, Roberto Cuevas; Delgado, Roberto Salgado; Atzori, Marco
The mammalian neocortex is a multilayered structure receiving extensive adrenergic projections both in rostral and caudal areas. The cellular mechanisms of norepinephrine (NE) in the neocortex are incompletely understood. We used electrophysiology to determine whether NE modulation of synaptic transmission were similar in rostral versus caudal cortical areas, and in infra- versus supra-granular cortical layers. To address these questions we used bath applications of NE (20 µM) to determine its effects on pharmacologically isolated electrically-evoked 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propionic acid receptor (AMPAR)-mediated excitatory synaptic currents (eEPSCs), or ?-amino butyric acid A receptor (GABAAR)-mediated inhibitory synaptic currents (eIPSCs). We monitored synaptic currents in pyramidal neurons using whole-cell patch-clamp recordings from supragranular layer 2/3 (L2/3) and infragranular layer 5 (L5) neurons in a thin-slice preparation of rat medial prefrontal cortex (mPFC). These results were compared with the effects in the temporal cortex (TC) under similar experimental conditions. We found that NE uniformly and transiently depressed eEPSCs from supragranular to infragranular layers in both the PFC and the TC. On the contrary, the effects of NE on eIPSC were area- and layer-dependent, as NE enhanced the mean amplitude in TC L2/3 and PFC L5 eIPSCs (which displayed the largest saturation currents in the areas studied) but depressed PFC L2/3 eIPSCs, without affecting TC L5 eIPSCs. While the precise physiological meaning of these results is still unclear, our data are consistent with the existence of a dense noradrenergic-controlled GABAergic cortical network in the PFC, in which L5 may act as a decisional bottleneck for behavioral inhibition. PMID:25266551
Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors
Parmelee, Caitlyn M.; Chen, Minghui; Cork, Karlene M.; Curto, Carina; Thoreson, Wallace B.
At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca2+) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant, ? = 1/(D??s), where D is the vesicle diffusion coefficient, ? is the vesicle diameter, ? is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higher-frequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons. PMID:25311636
Functional effects of somatostatin receptor 1 activation on synaptic transmission in the mouse hippocampus.
Cammalleri, Maurizio; Martini, Davide; Timperio, Anna Maria; Bagnoli, Paola
Somatostatin-14 (SRIF) co-localizes with GABA in the hippocampus and regulates neuronal excitability. A role of SRIF in the control of hippocampal activity has been proposed, although the exact contribution of each SRIF receptor (sst(1)-sst(5)) in mediating SRIF action requires some clarification. We used hippocampal slices of wild-type and sst(1) knockout (KO) mice and selective pharmacological tools to provide conclusive evidence for a role of sst(1) in mediating SRIF inhibition of synaptic transmission. With single- and double-label immunohistochemistry, we determined the distribution of sst(1) in hippocampal slices and we quantified sst(1) colocalization with SRIF. With electrophysiology, we found that sst(1) activation with CH-275 inhibited both the NMDA- and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated responses. Results from sst(1) KO slices confirmed the specificity of CH-275 effects; sst(1) activation did not affect the inhibitory transmission which was in contrast increased by sst(4) activation with L-803,087 in both wild-type and sst(1) KO slices. The AMPA-mediated responses were increased by L-803,087. Functional interaction between sst(1) and sst(4) is suggested by the finding that their combined activation prevented the CH-275-induced inhibition of AMPA transmission. The involvement of pre-synaptic mechanisms in mediating inhibitory effects of sst(1) on excitatory transmission was demonstrated by the finding that CH-275 (i) increased the paired-pulse facilitation ratio, (ii) did not influence the AMPA depolarization in the presence of tetrodotoxin, and (iii) inhibited glutamate release induced by epileptiform treatment. We conclude that SRIF control of excitatory transmission through an action at sst(1) may represent an important contribution to the regulation of hippocampal activity. PMID:19811607
Plasticity of synaptic connections in sensory-motor pathways of the adult locust flight system.
Wolf, H; Büschges, A
We investigated possible roles of retrograde signals and competitive interactions in the lesion-induced reorganization of synaptic contacts in the locust CNS. Neuronal plasticity is elicited in the adult flight system by removal of afferents from the tegula, a mechanoreceptor organ at the base of the wing. We severed one hindwing organ and studied the resulting rearrangement of synaptic contacts between flight interneurons and afferent neurons from the remaining three tegulae (2 forewing, 1 hindwing). This was done by electric stimulation of afferents and intracellular recording from interneurons (and occasionally motoneurons). Two to three weeks after unilateral tegula lesion, connections between tegula afferents and flight interneurons were altered in the following way. 1) Axons from the forewing tegula on the operated side had established new synaptic contacts with metathoracic elevator interneurons. In addition, the amplitude of compound excitatory postsynaptic potentials elicited by electric stimulation was increased, indicating that a larger number of afferents connected to any given interneuron. 2) On the side contralateral to the lesion, connectivity between axons from the forewing tegula and elevator interneurons was decreased. 3) The efficacy of the (remaining) hindwing afferents appeared to be increased with regard to both synaptic transmission to interneurons and impact on flight motor pattern. 4) Flight motoneurons, which are normally restricted to the ipsilateral hemiganglion, sprouted across the ganglion midline after unilateral tegula removal and apparently established new synaptic contacts with tegula afferents on that side. The changes on the operated side are interpreted as occupation of synaptic space vacated on the interneurons by the severed hindwing afferents. On the contralateral side, the changes in synaptic contact must be elicited by retrograde signals from bilaterally arborizing flight interneurons, because tegula projections remain strictly ipsilateral. The pattern of changes suggests competitive interactions between forewing and hindwing afferents. The present investigation thus presents evidence that the CNS of the mature locust is capable of extensive synaptic rearrangement in response to injury and indicates for the first time the action of retrograde signals from interneurons. PMID:9310419
Inhibitor of glutamate transport alters synaptic transmission at sensorimotor synapses in Aplysia.
Chin, Jeannie; Burdohan, John A; Eskin, Arnold; Byrne, John H
Aplysia sensory neurons possess high-affinity glutamate uptake activity that is regulated by serotonin. To gain insight into the physiological role of glutamate uptake in sensory neurons, we examined whether blockade of glutamate transport altered synaptic transmission. We also examined whether glutamate transport affected homosynaptic depression and posttetanic potentiation (PTP). In the presence of DL-threo-beta-hydroxyaspartic acid (THA), previously shown to block glutamate uptake in Aplysia, the duration of unitary excitatory postsynaptic potentials (EPSPs) was significantly increased and their amplitude was significantly reduced. Similar effects were observed in the properties of summated EPSPs. However, no effect on the induction of homosynaptic depression or PTP was observed. Although it is unclear whether THA exerted its effect by modulating neuronal and/or glial mechanisms, at least one target of THA was neuronal, as the duration of unitary EPSPs measured in cultured sensorimotor synapses was also increased in the presence of THA. These results support the hypotheses that glutamate is the transmitter released by the sensory neurons and that glutamate transport plays an important role in regulating features of synaptic transmission in Aplysia. PMID:12037218
Distinct neuronal coding schemes in memory revealed by selective erasure of fast synchronous synaptic transmission.
Xu, Wei; Morishita, Wade; Buckmaster, Paul S; Pang, Zhiping P; Malenka, Robert C; Südhof, Thomas C
Neurons encode information by firing spikes in isolation or bursts and propagate information by spike-triggered neurotransmitter release that initiates synaptic transmission. Isolated spikes trigger neurotransmitter release unreliably but with high temporal precision. In contrast, bursts of spikes trigger neurotransmission reliably (i.e., boost transmission fidelity), but the resulting synaptic responses are temporally imprecise. However, the relative physiological importance of different spike-firing modes remains unclear. Here, we show that knockdown of synaptotagmin-1, the major Ca(2+) sensor for neurotransmitter release, abrogated neurotransmission evoked by isolated spikes but only delayed, without abolishing, neurotransmission evoked by bursts of spikes. Nevertheless, knockdown of synaptotagmin-1 in the hippocampal CA1 region did not impede acquisition of recent contextual fear memories, although it did impair the precision of such memories. In contrast, knockdown of synaptotagmin-1 in the prefrontal cortex impaired all remote fear memories. These results indicate that different brain circuits and types of memory employ distinct spike-coding schemes to encode and transmit information. PMID:22405208
Effect of resiniferatoxin on glutamatergic spontaneous excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord
C.-Y. Jiang; T. Fujita; H.-Y. Yue; L.-H. Piao; T. Liu; T. Nakatsuka; E. Kumamoto
The transient receptor potential (TRP) vanilloid type 1 (TRPV1) agonist, capsaicin, enhances glutamatergic spontaneous excitatory synaptic transmission in CNS neurons. Resiniferatoxin (RTX) has a much higher affinity for TRPV1 than capsaicin, but its ability to modulate excitatory transmission is unclear. We examined the effect of RTX on excitatory transmission using the whole-cell patch-clamp technique in substantia gelatinosa (SG) neurons of
Serotonin is a facilitatory neuromodulator of synaptic transmission and "reinforces" long-term potentiation induction in the vertical lobe of Octopus vulgaris.
Shomrat, T; Feinstein, N; Klein, M; Hochner, B
The modern cephalopod mollusks (coleoids) are considered the most behaviorally advanced invertebrate, yet little is known about the neurophysiological basis of their behaviors. Previous work suggested that the vertical lobe (VL) of cephalopods is a crucial site for the learning and memory components of these behaviors. We are therefore studying the neurophysiology of the VL in Octopus vulgaris and have discovered a robust activity-dependent long-term potentiation (LTP) of the synaptic input to the VL. Moreover, we have shown that the VL and its LTP are involved in behavioral long-term memory acquisition. To advance our understanding of the VL as a learning neural network we explore the possible involvement of neuromodulation in VL function. Here we examine whether the well studied serotonergic modulation in simple models of learning in gastropods mollusks is conserved in the octopus VL. We demonstrate histochemically that the VL is innervated by afferent terminals containing 5-HT immunoreactivity (5-HT-IR). Physiologically, 5-HT has a robust facilitatory effect on synaptic transmission and activity-dependent LTP induction. These results suggest that serotonergic neuromodulation is a part of a reinforcing/reward signaling system conserved in both simple and complex learning systems of mollusks. However, there are notable functional differences. First, the effective concentration of 5-HT in the VL is rather high (100 microM); secondly, only neuropilar regions but not cell bodies in the VL are innervated by terminals containing 5-HT-IR. Thirdly, repetitive or long exposures to 5-HT do not lead to a clear long-term facilitation. We propose that in the octopus VL, while the basic facilitatory properties of molluscan 5-HT system are conserved, the system has adapted to convey signals from other brain areas to reinforce the activity-dependent associations at specific sites in the large connections matrix in the VL. PMID:20433903
M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission.
Sun, Jianli; Kapur, Jaideep
Previous studies have suggested that muscarinic receptor activation modulates glutamatergic transmission. M-type potassium channels mediate the effects of muscarinic activation in the hippocampus, and it has been proposed that they modulate glutamatergic synaptic transmission. We tested whether M1 muscarinic receptor activation enhances glutamatergic synaptic transmission via the inhibition of the M-type potassium channels that are present in Schaffer collateral axons and terminals. Miniature excitatory postsynaptic currents (mEPSCs) were recorded from CA1 pyramidal neurons. The M1 receptor agonist, NcN-A-343, increased the frequency of mEPSCs, but did not alter their amplitude. The M-channel blocker XE991 and its analogue linopirdine also increased the frequency of mEPSCs. Flupirtine, which opens M-channels, had the opposite effect. XE991 did not enhance mEPSCs frequency in a calcium-free external medium. Blocking P/Q- and N-type calcium channels abolished the effect of XE991 on mEPSCs. These data suggested that the inhibition of M-channels increases presynaptic calcium-dependent glutamate release in CA1 pyramidal neurons. The effects of these agents on the membrane potentials of presynaptic CA3 pyramidal neurons were studied using current clamp recordings; activation of M1 receptors and blocking M-channels depolarized neurons and increased burst firing. The input resistance of CA3 neurons was increased by the application of McN-A-343 and XE991; these effects were consistent with the closure of M-channels. Muscarinic activation inhibits M-channels in CA3 pyramidal neurons and its efferents – Schaffer collateral, which causes the depolarization, activates voltage-gated calcium channels, and ultimately elevates the intracellular calcium concentration to increase the release of glutamate on CA1 pyramidal neurons. PMID:22674722
Regulation and Restoration of Motoneuronal Synaptic Transmission During Neuromuscular Regeneration in the Pulmonate Snail Helisoma trivolvis
Turner, M. B.; Szabo-Maas, T. M.; Poyer, J. C.; Zoran, M. J.
Regeneration of motor systems involves reestablishment of central control networks, reinnervation of muscle targets by motoneurons, and reconnection of neuromodulatory circuits. Still, how these processes are integrated as motor function is restored during regeneration remains ill defined. Here, we examined the mechanisms underlying motoneuronal regeneration of neuromuscular synapses related to feeding movements in the pulmonate snail Helisoma trivolvis. Neurons B19 and B110, although activated during different phases of the feeding pattern, innervate similar sets of muscles. However, the percentage of muscle fibers innervated, the efficacy of excitatory junction potentials, and the strength of muscle contractions were different for each cell's specific connections. After peripheral nerve crush, a sequence of transient electrical and chemical connections formed centrally within the buccal ganglia. Neuromuscular synapse regeneration involved a three-phase process: the emergence of spontaneous synaptic transmission (P1), the acquisition of evoked potentials of weak efficacy (P2), and the establishment of functional reinnervation (P3). Differential synaptic efficacy at muscle contacts was recapitulated in cell culture. Differences in motoneuronal presynaptic properties (i.e., quantal content) were the basis of disparate neuromuscular synapse function, suggesting a role for retrograde target influences. We propose a homeostatic model of molluscan motor system regeneration. This model has three restoration events: (1) transient central synaptogenesis during axonal outgrowth, (2) intermotoneuronal inhibitory synaptogenesis during initial neuromuscular synapse formation, and (3) target-dependent regulation of neuromuscular junction formation. PMID:21876114
An intact peripheral nerve preparation for monitoring the activity of single, periosteal afferent nerve fibres.
Mahns, David A; Ivanusic, Jason J; Sahai, Vineet; Rowe, Mark J
A preparation is described in which it is possible to selectively activate and monitor the activity of the individual periosteal afferent nerve fibres arising from the humerus bone of the cat. The nerve is a fine branch of the median nerve that accompanies the small artery and vein that enter the nutrient foramen of the humerus. By freeing this fine nerve from nearby tissue over a length of approximately 1-2 cm and placing it over a silver hook recording electrode, it becomes possible to identify and monitor electrophysiologically, the impulse activity of individual periosteal afferent fibres activated by focal mechanical stimulation of the periosteum. With this preparation it will be possible to examine the central actions and security of transmission at central synaptic targets for single, small-diameter afferent fibres arising from bone. PMID:16574241
Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission.
Zhang, Mingming; Ladas, Thomas P; Qiu, Chen; Shivacharan, Rajat S; Gonzalez-Reyes, Luis E; Durand, Dominique M
The propagation of activity in neural tissue is generally associated with synaptic transmission, but epileptiform activity in the hippocampus can propagate with or without synaptic transmission at a speed of ?0.1 m/s. This suggests an underlying common nonsynaptic mechanism for propagation. To study this mechanism, we developed a novel unfolded hippocampus preparation, from CD1 mice of either sex, which preserves the transverse and longitudinal connections and recorded activity with a penetrating microelectrode array. Experiments using synaptic transmission and gap junction blockers indicated that longitudinal propagation is independent of chemical or electrical synaptic transmission. Propagation speeds of 0.1 m/s are not compatible with ionic diffusion or pure axonal conduction. The only other means of communication between neurons is through electric fields. Computer simulations revealed that activity can indeed propagate from cell to cell solely through field effects. These results point to an unexpected propagation mechanism for neural activity in the hippocampus involving endogenous field effect transmission. PMID:24453330
DAMGO depresses inhibitory synaptic transmission via different downstream pathways of ? opioid receptors in ventral tegmental area and periaqueductal gray.
Zhang, W; Yang, H L; Song, J J; Chen, M; Dong, Y; Lai, B; Yu, Y G; Ma, L; Zheng, P
Opioid-induced rewarding and motorstimulant effects are mediated by an increased activity of the ventral tegmental area (VTA) dopamine (DA) neurons. The excitatory mechanism of opioids on VTA-DA neurons has been proposed to be due to the depression of GABAergic synaptic transmission in VTA-DA neurons. However, how opioids depress GABAergic synaptic transmission in VTA-DA neurons remain to be studied. In the present study, we explored the mechanism of the inhibitory effect of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on GABAergic synaptic transmission in VTA-DA neurons using multiple approaches and techniques. Our results showed that (1) DAMGO inhibits GABAergic inputs in VTA-DA neurons at presynaptic sites; (2) effect of DAMGO on GABAergic inputs in VTA-DA neurons is inhibited by potassium channel blocker 4-aminopyridine (4-AP) and Gi protein inhibitor N-ethylmaleimide (NEM); (3) phospholipase A2 (PLA2) does not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons, but mediates it in the periaqueductal gray (PAG); (4) multiple downstream signaling molecules of ? receptors do not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons. These results suggest that DAMGO depresses inhibitory synaptic transmission via ? receptor-Gi protein-Kv channel pathway in VTA-DA neurons, but via ? receptor-PLA2 pathway in PAG neurons. PMID:26047721
5-HT inhibits calcium current and synaptic transmission from sensory neurons in lamprey.
El Manira, A; Zhang, W; Svensson, E; Bussičres, N
In the lamprey spinal cord, 5-hydroxytryptamine (5-HT) immunoreactivity (ir) is present in the ventromedial plexus originating from intraspinal neurons, ventrolateral column arising from the brainstem, and dorsal column. The latter 5-HT system originates from small dorsal root ganglion neurons. Combined Lucifer yellow intracellular labeling of the intraspinal sensory neurons, dorsal cells, and 5-HT immunohistochemistry showed close appositions between 5-HT-ir fibers and dorsal cell axons. Application of 5-HT depressed monosynaptic EPSPs evoked in giant interneurons by stimulation of single dorsal cells, dorsal roots, or dorsal column without any detectable change in the input resistance of postsynaptic neurons. Furthermore, the amplitude of AMPA-evoked depolarizations in giant interneurons was unaffected by 5-HT. The lack of postsynaptic effects of 5-HT indicates that the decrease of the amplitude of sensory monosynaptic EPSPs by 5-HT is mediated by presynaptic mechanisms. The inhibition of monosynaptic EPSPs by 5-HT was not counteracted by an antagonist of 5-HT1A receptors. 5-HT also reduced the amplitude of the calcium current recorded in isolated dorsal cells and slowed down its kinetics. The inhibition of calcium channels could represent the mechanism mediating the depression of synaptic transmission at the axonal level. These results show that activation of 5-HT receptors on dorsal cell axons as well as on other sensory neurons mediates inhibition of sensory synaptic transmission to giant interneurons. In intact animals, 5-HT could be released from small 5-HT neurons in dorsal root ganglia, which thus may underlie direct sensory-sensory interactions. PMID:9030637
Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse
Halstead, James M.; Lin, Yong Qi; Durraine, Lita; Hamilton, Russell S.; Ball, Graeme; Neely, Greg G.; Bellen, Hugo J.; Davis, Ilan
ABSTRACT Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation. PMID:25171887
Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmission.
Hickman, John A; Hardwick, J Marie; Kaczmarek, Leonard K; Jonas, Elizabeth A
A role for BCL-xL in regulating neuronal activity is suggested by its dramatic effects on synaptic function and mitochondrial channel activity. When recombinant BCL-xL is injected into the giant presynaptic terminal of squid stellate ganglion or applied directly to mitochondrial outer membranes within the living terminal, it potentiates synaptic transmission acutely, and it produces mitochondrial channel activity. The squid, however, is a genetically intractable model, making it difficult to apply genetic tools in squid to explore the role of endogenous BCL-xL in synaptic function. Therefore the small molecule inhibitor ABT-737, a mimetic of the BH3-only protein BAD, binding to the BH3-binding domain pocket, was tested in squid, revealing a dual role for BCL-xL. ABT-737 slowed recovery of synaptic responses after repetitive synaptic activity, indicating that endogenous BCL-xL is necessary for timely recovery of rapidly firing synapses. Unexpectedly, however, ABT-737 also protected neurons from hypoxia-induced synaptic rundown and from increased permeability of the mitochondrial outer membrane during hypoxia. This implies that endogenous BCL-xL or a modified form of BCL-xL, such as the N-truncated, proteolytic, pro-apoptotic cleavage product, DeltaN BCL-xL, contributes to injurious responses of the hypoxic synapse. To determine if ABT-737 is also an inhibitor of DeltaN BCL-xL, recombinant DeltaN BCL-xL protein was injected into the synapse. ABT-737 potently inhibited synaptic rundown induced by recombinant DeltaN BCL-xL. These observations support the possibility that endogenous proteolysis or a functionally equivalent modification of BCL-xL is responsible for the deleterious effects of hypoxia on synaptic activity. PMID:18160428
Tachykininergic synaptic transmission in the coeliac ganglion of the guinea-pig.
Zhao, F. Y.; Saito, K.; Yoshioka, K.; Guo, J. Z.; Murakoshi, T.; Konishi, S.; Otsuka, M.
1. The responses of coeliac ganglion neurones of the guinea-pig to electrical stimulation of the mesenteric nerves and applications of tachykinin receptor agonists were investigated by use of intracellular recording techniques. 2. Ganglion neurones were classified into three groups based on firing patterns in response to a depolarizing current pulse: phasic (38% of the population), tonic (39%) and atypical (23%). In the majority of phasic neurones (91%) a long after-hyperpolarization (LAH) lasting 5-8 s followed action potentials induced by a train of depolarizing current pulses. In contrast, LAH was rarely observed in tonic neurones (5%). 3. In most of tonic neurones (90%) slow excitatory post-synaptic potentials (e.p.s.ps) lasting 3-10 min were evoked by repetitive electrical stimulation of the mesenteric nerves. Prolonged depolarizations were also evoked in most tonic neurones by applications of substance P (SP), neurokinin A (NKA) or senktide, a tachykinin NK3 receptor agonist. 4. In most of phasic neurones (73%), mesenteric nerve stimulation did not induce an obvious depolarization but induced a prolonged inhibition of LAH lasting 3-10 min. Bath-applied tachykinin receptor agonists similarly induced an inhibition of LAH without causing depolarization in most of the phasic neurones. 5. GR 71251 (5 microM), a tachykinin NK1 receptor antagonist, partially depressed the nerve-evoked slow e.p.s.ps in tonic neurones and the nerve-evoked LAH inhibition in phasic neurones. 6. Capsaicin (0.1-5 microM) induced a prolonged depolarization in tonic neurones and an inhibition of LAH in phasic neurones. 7. A mixture of peptidase inhibitors potentiated the depolarization and the LAH inhibition evoked by nerve stimulation, SP and NKA, but not those evoked by senktide. 8. It is concluded that tonic neurones respond to repetitive mesenteric nerve stimulation preferentially with slow e.p.s.ps and that phasic neurones respond preferentially with LAH inhibition. The present study further suggests that SP and NKA, released from axon collaterals of primary afferent neurones, produce slow e.p.s.ps in tonic neurones and the LAH inhibition in phasic neurones via NK1 receptors. PMID:8864543
Synaptic Ribbon Enables Temporal Precision of Hair Cell Afferent Synapse by Increasing the Number of Readily Releasable Vesicles: A Modeling Study
Wittig, John H.; Parsons, Thomas D.
Synaptic ribbons are classically associated with mediating indefatigable neurotransmitter release by sensory neurons that encode persistent stimuli. Yet when hair cells lack anchored ribbons, the temporal precision of vesicle fusion and auditory nerve discharges are degraded. A rarified statistical model predicted increasing precision of first-exocytosis latency with the number of readily releasable vesicles. We developed an experimentally constrained biophysical model to test the hypothesis that ribbons enable temporally precise exocytosis by increasing the readily releasable pool size. Simulations of calcium influx, buffered calcium diffusion, and synaptic vesicle exocytosis were stochastic (Monte Carlo) and yielded spatiotemporal distributions of vesicle fusion consistent with experimental measurements of exocytosis magnitude and first-spike latency of nerve fibers. No single vesicle could drive the auditory nerve with requisite precision, indicating a requirement for multiple readily releasable vesicles. However, plasmalemma-docked vesicles alone did not account for the nerve's precision—the synaptic ribbon was required to retain a pool of readily releasable vesicles sufficiently large to statistically ensure first-exocytosis latency was both short and reproducible. The model predicted that at least 16 readily releasable vesicles were necessary to match the nerve's precision and provided insight into interspecies differences in synaptic anatomy and physiology. We confirmed that ribbon-associated vesicles were required in disparate calcium buffer conditions, irrespective of the number of vesicles required to trigger an action potential. We conclude that one of the simplest functions ascribable to the ribbon—the ability to hold docked vesicles at an active zone—accounts for the synapse's temporal precision. PMID:18667546
Role of NMDA receptors in the lateralized potentiation of amygdala afferent and efferent neural transmission produced by predator stress
Robert Adamec; Jacqueline Blundell; Paul Burton
The present study investigated the role of NMDA receptors in behavioral and neuroplastic changes in amygdala efferent (central amygdala to periaqueductal gray–ACE–PAG) and amygdala afferent (ventral angular bundle to basolateral amygdala–VAB–BLA) pathways in response to predator stress. Effects on brain and behavioral response to predator stress of competitive block of NMDA receptors with a dose of 10 mg\\/kg of CPP
Distinct Neuronal Coding Schemes in Memory Revealed by Selective Erasure of Fast Synchronous Synaptic Transmission
Xu, Wei; Morishita, Wade; Buckmaster, Paul S.; Pang, Zhiping P.; Malenka, Robert C.; Südhof, Thomas C.
Neurons encode information by firing spikes in isolation or bursts, and propagate information by spike-triggered neurotransmitter release that initiates synaptic transmission. Isolated spikes trigger neurotransmitter release unreliably but with high temporal precision, whereas bursts of spikes boost transmission fidelity by overcoming the unreliability of spike-triggered release but are temporally imprecise. However, the relative physiological importance of different spike firing modes remains unclear. Here, we show that knockdown of synaptotagmin-1, the major Ca2+-sensor for neurotransmitter release, abrogated neurotransmission evoked by isolated spikes, but only delayed without abolishing neurotransmission evoked by bursts of spikes. Nevertheless, knockdown of synaptotagmin-1 in the hippocampal CA1 region did not impede acquisition of recent contextual fear memories, although it did impair the precision of such memories. In contrast, knockdown of synaptotagmin-1 in the prefrontal cortex impaired all remote fear memories. These results indicate that different brain circuits and types of memory employ distinct spike-coding schemes to encode and transmit information. PMID:22405208
Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels
Klaassen, Lauw J.; Sun, Ziyi; Steijaert, Marvin N.; Bolte, Petra; Fahrenfort, Iris; Sjoerdsma, Trijntje; Klooster, Jan; Claassen, Yvonne; Shields, Colleen R.; Ten Eikelder, Huub M. M.; Janssen-Bienhold, Ulrike; Zoidl, Georg; McMahon, Douglas G.; Kamermans, Maarten
In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina. PMID:21811399
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Appenzeller, Silke; Balling, Rudi; Barisic, Nina; Baulac, Stéphanie; Caglayan, Hande; Craiu, Dana; De Jonghe, Peter; Depienne, Christel; Dimova, Petia; Djémié, Tania; Gormley, Padhraig; Guerrini, Renzo; Helbig, Ingo; Hjalgrim, Helle; Hoffman-Zacharska, Dorota; Jähn, Johanna; Klein, Karl Martin; Koeleman, Bobby; Komarek, Vladimir; Krause, Roland; Kuhlenbäumer, Gregor; Leguern, Eric; Lehesjoki, Anna-Elina; Lemke, Johannes R.; Lerche, Holger; Linnankivi, Tarja; Marini, Carla; May, Patrick; Mřller, Rikke S.; Muhle, Hiltrud; Pal, Deb; Palotie, Aarno; Pendziwiat, Manuela; Robbiano, Angela; Roelens, Filip; Rosenow, Felix; Selmer, Kaja; Serratosa, Jose M.; Sisodiya, Sanjay; Stephani, Ulrich; Sterbova, Katalin; Striano, Pasquale; Suls, Arvid; Talvik, Tiina; von Spiczak, Sarah; Weber, Yvonne; Weckhuysen, Sarah; Zara, Federico; Abou-Khalil, Bassel; Alldredge, Brian K.; Andermann, Eva; Andermann, Frederick; Amron, Dina; Bautista, Jocelyn F.; Berkovic, Samuel F.; Bluvstein, Judith; Boro, Alex; Cascino, Gregory; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P.; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Geller, Eric B.; Glauser, Tracy; Glynn, Simon; Haas, Kevin; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Eric H.; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H.; McGuire, Shannon M.; Motika, Paul V.; Novotny, Edward J.; Ottman, Ruth; Paolicchi, Juliann M.; Parent, Jack; Park, Kristen; Poduri, Annapurna; Sadleir, Lynette; Scheffer, Ingrid E.; Shellhaas, Renée A.; Sherr, Elliott; Shih, Jerry J.; Singh, Rani; Sirven, Joseph; Smith, Michael C.; Sullivan, Joe; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P.G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.; Allen, Andrew S.; Berkovic, Samuel F.; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E.; Epstein, Michael P.; Glauser, Tracy; Goldstein, David B.; Han, Yujun; Heinzen, Erin L.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Marson, Anthony G.; Mefford, Heather C.; Nieh, Sahar Esmaeeli; O'Brien, Terence J.; Ottman, Ruth; Petrou, Stephen; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K.; Scheffer, Ingrid E.; Sherr, Elliott
Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10?4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction. PMID:25262651
Long-term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP.
Briggs, C. A.; McAfee, D. A.; McCaman, R. E.
1. Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response. 2. The beta-adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz. 3. The adenosine receptor agonist 2-chloroadenosine inhibited ACh release and the postganglionic response by about 35%. 4. Tetanic preganglionic stimulation for a few seconds induced a long-term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani. 5. Forskolin and analogues of cyclic AMP also caused a long-lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl- and bromo-purine nucleotides. 6. The effects of forskolin and 8-bromo-cyclic AMP did not appear to be dependent upon extracellular Ca2+. 7. The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors--AH 21-132, papaverine and SQ 20-006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22-536. 8. The neurogenic long-term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin-induced potentiation--papaverine and SQ 20-006. 9. It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long-term potentiation induced by tetanic preganglionic stimulation. PMID:2833971
Rabconnectin3? promotes stable activity of the H+-pump on synaptic vesicles in hair cells
Einhorn, Zev; Trapani, Josef G.; Liu, Qianyong; Nicolson, Teresa
Acidification of synaptic vesicles relies on the Vacuolar-type ATPase (V-ATPase), which provides the electrochemical driving force for neurotransmitter exchange. The regulatory mechanisms that ensure assembly of the V-ATPase holoenzyme on synaptic vesicles are unknown. Rabconnectin3? (Rbc3?) is a potential candidate for regulation of V-ATPase activity because of its association with synaptic vesicles and its requirement for acidification of intracellular compartments. Here, we provide the first evidence for a role of Rbc3? in synaptic vesicle acidification and neurotransmission. In this study, we characterized mutant alleles of rbc3? isolated from a large-scale screen for zebrafish with auditory/vestibular defects. We show that Rbc3? is localized to basal regions of hair cells where synaptic vesicles are present. To determine whether Rbc3? regulates V-ATPase activity, we examined the acidification of synaptic vesicles and localization of the V-ATPase in hair cells. In contrast to wild-type hair cells, we observed that synaptic vesicles had elevated pH and a cytosolic subunit of the V-ATPase was no longer enriched in synaptic regions of mutant hair cells. As a consequence of defective acidification of synaptic vesicles, afferent neurons in rbc3? mutants had reduced firing rates and reduced accuracy of phase-locked action potentials in response to mechanical stimulation of hair cells. Collectively, our data suggest that Rbc3? modulates synaptic transmission in hair cells by promoting V-ATPase activity in synaptic vesicles. PMID:22875945
Delayed Reduction of Hippocampal Synaptic Transmission and Spines Following Exposure to Repeated Subclinical Doses of Organophosphorus Pesticide in Adult Mice
Speed, Haley E.; Blaiss, Cory A.; Kim, Ahleum; Haws, Michael E.; Melvin, Neal R.; Jennings, Michael; Eisch, Amelia J.; Powell, Craig M.
Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2–7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2–7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo. PMID:21948870
Regulation of Synaptic Transmission at the Caenorhabditis elegans M4 Neuromuscular Junction by an Antagonistic Relationship Between Two Calcium Channels
Steciuk, Mark; Cheong, Mi Cheong; Waite, Christopher; You, Young-Jai; Avery, Leon
In wild-type Caenorhabditis elegans, the synapse from motor neuron M4 to pharyngeal terminal bulb (TB) muscles is silent, and the muscles are instead excited by gap junction connections from adjacent muscles. An eat-5 innexin mutant lacking this electrical connection has few TB contractions and is unable to grow well on certain foods. We showed previously that this defect can be overcome by activation of the M4 ? TB synapse. To identify genes that negatively regulate synaptic transmission, we isolated new suppressors of eat-5. To our surprise, these suppressors included null mutations in NPQR-type calcium channel subunit genes unc-2 and unc-36. Our results are consistent with the hypothesis that Ca2+ entry through the NPQR-type channel inhibits synaptic transmission by activating the calcium-activated K+ channel SLO-1, thus antagonizing the EGL-19 L-type calcium channel. PMID:25378475
Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices.
Berger, F; Hensel, A; Nieber, K
Saffron, the dried stigmata of Crocus sativus L., is used in traditional medicine for a wide range of indications including cramps, asthma, and depression. To investigate the influence of hydro-ethanolic saffron extract (CSE) and trans-crocetin on synaptic transmission, postsynaptic potentials (PSPs) were elicited by focal electrical stimulation and recorded using intracellular placed microelectrodes in pyramidal cells from rat cingulate cortex. CSE (10-200 ?g/ml) inhibited evoked PSPs as well as the isolated NMDA and non-NMDA component of PSPs. Glutamate (500 ?M) added into the organ bath induced membrane depolarization. CSE decreased glutamate-induced membrane depolarization. Additionally, CSE at 100 ?g/ml decreased NMDA (20 ?M) and kainate (1 ?M)-induced depolarization, whereas AMPA (1 ?M)-induced depolarization was not affected. Trans-crocetin (1-50 ?M) showed inhibition of evoked PSPs and glutamate-induced membrane depolarization comparable to CSE. Trans-crocetin at 10 ?M decreased NMDA (20 ?M)-induced membrane depolarization, but did not inhibit the isolated non-NMDA component of PSPs. We conclude that trans-crocetin is involved in the antagonistic effect of CSE on NMDA but not on kainate receptors. PMID:21352900
The quantal component of synaptic transmission from sensory hair cells to the vestibular calyx.
Highstein, Stephen M; Mann, Mary Anne; Holstein, Gay R; Rabbitt, Richard D
Spontaneous and stimulus-evoked excitatory postsynaptic currents (EPSCs) were recorded in calyx nerve terminals from the turtle vestibular lagena to quantify key attributes of quantal transmission at this synapse. On average, EPSC events had a magnitude of ?42 pA, a rise time constant of ?0 ?229 ?s, decayed to baseline with a time constant of ?R ?690 ?s, and carried ?46 fC of charge. Individual EPSCs varied in magnitude and decay time constant. Variability in the EPSC decay time constant was hair cell dependent and due in part to a slow protraction of the EPSC in some cases. Variability in EPSC size was well described by an integer summation of unitary quanta, with each quanta of glutamate gating a unitary postsynaptic current of ?23 pA. The unitary charge was ?26 fC for EPSCs with a simple exponential decay and increased to ?48 fC for EPSCs exhibiting a slow protraction. The EPSC magnitude and the number of simultaneous unitary quanta within each event increased with presynaptic stimulus intensity. During tonic hair cell depolarization, both the EPSC magnitude and event rate exhibited adaptive run down over time. Present data from a reptilian calyx are remarkably similar to noncalyceal vestibular synaptic terminals in diverse species, indicating that the skewed EPSC size distribution and multiquantal release might be an ancestral property of inner ear ribbon synapses. PMID:25878150
Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex
López-Ramos, Juan Carlos; Guerra-Narbona, Rafael; Delgado-García, José M.
Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals' avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations. PMID:25688195
Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission
Susanne Birnstiel; Ernst Wülfert; Sheryl G. Beck
Previous behavioural and electrophysiological studies have indicated that levetiracetam (ucb LO59) acts as an anticonvulsant\\u000a drug in vivo. The purpose of the present study was to investigate the effects of levetiracetam on normal synaptic transmission\\u000a and epileptiform activity in vitro. Intracellular recordings were obtained from the CA3 subfield of the rat hippocampal slice\\u000a preparation. Levetiracetam in a concentration of 10
Synaptic Transmission at Functionally Identified Synapses in the Enteric Nervous System: Roles for Both Ionotropic and Metabotropic Receptors
Gwynne, RM; Bornstein, JC
Digestion and absorption of nutrients and the secretion and reabsorption of fluid in the gastrointestinal tract are regulated by neurons of the enteric nervous system (ENS), the extensive peripheral nerve network contained within the intestinal wall. The ENS is an important physiological model for the study of neural networks since it is both complex and accessible. At least 20 different neurochemically and functionally distinct classes of enteric neurons have been identified in the guinea pig ileum. These neurons express a wide range of ionotropic and metabotropic receptors. Synaptic potentials mediated by ionotropic receptors such as the nicotinic acetylcholine receptor, P2X purinoceptors and 5-HT3 receptors are seen in many enteric neurons. However, prominent synaptic potentials mediated by metabotropic receptors, like the P2Y1 receptor and the NK1 receptor, are also seen in these neurons. Studies of synaptic transmission between the different neuron classes within the enteric neural pathways have shown that both ionotropic and metabotropic synaptic potentials play major roles at distinct synapses within simple reflex pathways. However, there are still functional synapses at which no known transmitter or receptor has been identified. This review describes the identified roles for both ionotropic and metabotropic neurotransmission at functionally defined synapses within the guinea pig ileum ENS. It is concluded that metabotropic synaptic potentials act as primary transmitters at some synapses. It is suggested identification of the interactions between different synaptic potentials in the production of complex behaviours will require the use of well validated computer models of the enteric neural circuitry. PMID:18615154
Comparison of pharmacological agents (aspartate vs. aminophosphonobutyric plus kynurenic acids) to block synaptic transmission from retinal photoreceptors in frog.
Xu, X J; Xu, J; Huang, B; Livsey, C T; Karwoski, C J
The combination of aminophosphonobutyric plus kynurenic acids (APB/Kyn) was compared to aspartate with respect to its ability to block synaptic transmission from photoreceptors. Like aspartate, APB/Kyn blocks photoreceptor synaptic transmission, as monitored by the b- and d-waves of the electroretinogram, by the proximal negative response and M-wave of the proximal retina, and by the light-evoked increase in extracellular K+ concentration in the inner plexiform layer. Unlike aspartate, APB/Kyn has relatively minor effects on retinal resistance, light-evoked changes in K+ and Ca2+ concentrations in the subretinal space, light-evoked changes in subretinal space volume, resting extracellular concentrations of K+ and Ca2+ in the proximal and distal retina, and the c-wave. Effects of APB/Kyn are generally more reversible than effects of Asp. A disadvantage of APB/Kyn is that the a-wave usually becomes smaller and slower. Overall, APB/Kyn disrupts the retina less than aspartate. Therefore, in some situations in which blockade of photoreceptor synaptic transmission is desired, the use of APB/Kyn may be preferable to that of aspartate. PMID:1649766
Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation.
Griffith, William H; Dubois, Dustin W; Fincher, Annette; Peebles, Kathryn A; Bizon, Jennifer L; Murchison, David
Basal forebrain (BF) cholinergic neurons participate in a number of cognitive processes that become impaired during aging. We previously found that age-related enhancement of Ca(2+) buffering in rat cholinergic BF neurons was associated with impaired performance in the water maze spatial learning task (Murchison D, McDermott AN, Lasarge CL, Peebles KA, Bizon JL, and Griffith WH. J Neurophysiol 102: 2194-2207, 2009). One way that altered Ca(2+) buffering could contribute to cognitive impairment involves synaptic function. In this report we show that synaptic transmission in the BF is altered with age and cognitive status. We have examined the properties of spontaneous postsynaptic currents (sPSCs) in cholinergic BF neurons that have been mechanically dissociated without enzymes from behaviorally characterized F344 rats. These isolated neurons retain functional presynaptic terminals on their somata and proximal dendrites. Using whole cell patch-clamp recording, we show that sPSCs and miniature PSCs are predominately GABAergic (bicuculline sensitive) and in all ways closely resemble PSCs recorded in a BF in vitro slice preparation. Adult (4-7 mo) and aged (22-24 mo) male rats were cognitively assessed using the water maze. Neuronal phenotype was identified post hoc using single-cell RT-PCR. The frequency of sPSCs was reduced during aging, and this was most pronounced in cognitively impaired subjects. This is the same population that demonstrated increased intracellular Ca(2+) buffering. We also show that increasing Ca(2+) buffering in the synaptic terminals of young BF neurons can mimic the reduced frequency of sPSCs observed in aged BF neurons. PMID:24133226
Liprin-?2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission
Spangler, Samantha A.; Schmitz, Sabine K.; Kevenaar, Josta T.; de Graaff, Esther; de Wit, Heidi; Demmers, Jeroen
The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-?2 as a key organizer in this process. We show that liprin-?2 levels were regulated by synaptic activity and the ubiquitin–proteasome system. Furthermore, liprin-?2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-?2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-?2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-?2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-?2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity. PMID:23751498
Properties of synaptic transmission at the neuromuscular junction of the squid, Loligo opalescens.
Stockbridge, N; Stockbridge, L L
1. Spontaneous and evoked synaptic activity were recorded from the muscles of squid fin and mantle. These spontaneous synaptic potentials were large (up to 30 mV) and pleomorphic. Their amplitudes were not normally distributed, nor did they appear to be clustered in integral multiples of some "unit" event size. 2. Electrical stimulation of the nerve resulted in muscle twitches when the bath calcium concentration was a third normal or higher. The frequency of spontaneous synaptic events was unaffected by low calcium. 3. The large size of spontaneous events may mean that the synchronized release of only a few such "quanta" are sufficient to cause muscle action potentials and contraction. 4. The shapes of spontaneous events correlated poorly with their amplitudes, which is consistent with release from multiple synaptic sites with distinct properties. PMID:2906836
Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.
Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru
In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817
[The role of synaptic transmission in memory and neurodegeneration processes and effects of neurotropic preparations].
Voronina, T A
Academician Zakusov, in his book Pharmacology of Central Synapses (Moscow, 1973), emphasized the central role of synaptic processes in regulation of various forms of behavior, memory, and psychotropic drug action. The paper considers most promising directions in the search for substances possessing nootropic and neuroprotector properties, many of which were developed at the Institute of Pharmacology based on the notion about synaptic processes. These investigations led to the creation of well-known drugs such as mexidole, noopept, nooglutyl, beglimin, etc. Special attention is devoted to the implementation and modern development of the ideas of Academician Zakusov. Recent data are presented on the role of neuropeptides, neurotrophins, and intracellular signaling mechanisms in synaptic plasticity, memory processes, and development of neurodegenerative states. PMID:12962041
Altered Hippocampal Synaptic Transmission in Transgenic Mice with Astrocyte-targeted Enhanced CCL2 Expression
Nelson, Thomas E.; Hao, Christine; Manos, Jessica; Ransohoff, R.M.; Gruol, Donna L.
Elevated expression of neuroinflammatory factors in the central nervous system (CNS) contributes to the cognitive impairment in CNS disorders such as injury, disease and neurodegenerative disorders. However, information on the role of specific neuroimmune factors in normal and abnormal CNS function is limited. In this study, we investigated the effects of chronic exposure to the chemokine CCL2 on hippocampal synaptic function at the Schaffer collateral-CA1 synapse, a synapse that is known to play an important role in cognitive functions such as memory and learning. Synaptic function was measured in vitro using hippocampal slices obtained from transgenic mice that express elevated levels of CCL2 in the CNS through astrocyte expression and their non-transgenic littermate controls. Extracellular field potential electrophysiological recordings showed a significant reduction in the magnitude of synaptic responses in hippocampal slices from the CCL2 transgenic mice compared with slices from non-transgenic littermate controls. Two forms of short-term synaptic plasticity (post-tetanic potentiation and short-term potentiation) thought to be important cellular mechanisms of short-term memory were enhanced in hippocampal slices from CCL2 transgenic mice compared to non-transgenic hippocampal slices, whereas long-term synaptic plasticity (LTP), which is critical to long-term memory formation, was not altered. Western blot analysis of hippocampus from the CCL2 transgenic mice and non-transgenic mice showed no change in level of neuronal specific enolase, a neuronal specific protein, GFAP, an astrocyte specific protein, and several synaptic proteins compared with non-transgenic littermate controls. These results show that CCL2, which is known to be chronically produced at elevated levels within the CNS in a number of CNS disorders, can significantly alter hippocampal function and implicate a role for CCL2 in the cognitive dysfunction associated with these CNS disorders. PMID:21356306
NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity
Declan W Ali; Michael W Salter
Regulation of postsynaptic glutamate receptors is one of the main mechanisms for altering synaptic efficacy in the central nervous system. Recent studies have given insight into the upregulation of the NMDA receptor by Src family tyrosine kinases, which bind to scaffolding proteins in the NMDA receptor complex. Src acts as a common step in signalling cascades that link G-protein-coupled receptors
Recombinant BDNF Rescues Deficits in Basal Synaptic Transmission and Hippocampal LTP in BDNF Knockout Mice
Susan L Patterson; Ted Abel; Thomas A. S Deuel; Kelsey C Martin; Jack C Rose; Eric R Kandel
Brain-derived neurotrophic factor (BDNF) is expressed at high levels in hippocampal neurons, and its expression is modulated by neural activity. Knockout mice can be used to study the roles of molecules like BDNF in synaptic plasticity with more molecular specificity than is possible using pharmacological approaches. Because in conventional knockouts the disrupted gene product is absent in all tissues throughout
Comparison of effects of monoamines on transmission in spinal pathways from group I and II muscle afferents in the cat
H. Bras; P. Cavallari; E. Jankowska; D. McCrea
The actions of noradrenaline (NA) and 5-hydroxytryptamine (5-HT; serotonin) were compared with those of L-3,4-dihydroxyphenylalanine methyl ester (Methyl-L-DOPA) on transmission to spinal interneurones in mid-lumbar (L4 and L5) segments of the cat spinal cord. The drugs were applied ionophoretically and their effects were tested on monosynaptic field potentials evoked by nerve impulses in hindlimb group I and group II muscle
Neurokinin-1 and -3 receptor blockade inhibits slow excitatory synaptic transmission in myenteric neurons and reveals slow inhibitory input.
Johnson, P J; Bornstein, J C
Recent studies have shown that tachykinins mediate slow synaptic transmission to myenteric AH (afterhyperpolarising) neurons via neurokinin-3 receptors (NK(3)R). This study investigated a similar role for neurokinin-1 receptors (NK(1)R) and compared the effect of selective receptor antagonists on non-cholinergic slow excitatory post-synaptic potentials (EPSPs) recorded in myenteric AH neurons of the guinea-pig ileum. Slow EPSPs evoked by electrical stimulation of circumferentially oriented presynaptic nerves were mimicked by application of senktide, an NK(3)R agonist. [Sar(9),Met(O(2))(11)]-substance P, an NK(1)R agonist, depolarised a smaller number of neurons. SR142801, a selective NK(3)R antagonist (100 nM), inhibited slow EPSPs and responses to senktide, but had no effect on depolarisations evoked by forskolin, an activator of adenylate cyclase. SR140333, a selective NK(1)R antagonist, inhibited slow EPSPs in a subset of neurons and blocked responses to [Sar(9),Met(O(2))(11)]-substance P, but not to senktide or forskolin. Slow EPSPs that were predominantly mediated by NK(1)R had significantly shorter latencies than those due to activation of NK(3)R. After blockade of slow EPSPs, slow hyperpolarizing responses to presynaptic nerve stimulation were revealed in one-third of neurons. These events, which were associated with a decrease in input resistance and blocked by tetrodotoxin, were equated with slow inhibitory postsynaptic potentials. They were abolished by the 5-hydroxytryptamine(1A) receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), but unaffected by phentolamine, an alpha-adrenoceptor antagonist. In conclusion, these results provide the first direct evidence that NK(1)R mediate some slow excitatory synaptic input to myenteric AH neurons, and suggest that NK(1)R and NK(3)R activate distinct signal transduction pathways. These results also demonstrate that slow inhibitory synaptic transmission, which may be mediated by 5-hydroxytryptamine, is more prevalent in the myenteric plexus than previously indicated. PMID:15145080
Postnatal Loss of P/Q-type Channels Confined to Rhombic Lip Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates Genomic Cacna1a Mutation Phenotype of Ataxia and Seizures in Mice
Maejima, Takashi; Wollenweber, Patric; Teusner, Lena U. C.; Noebels, Jeffrey L.; Herlitze, Stefan; Mark, Melanie D.
Ataxia, episodic dyskinesia and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca2+ channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We recently showed that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this paper, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic lip derived neurons including PF- and MF-pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function. PMID:23516282
The Excitatory Synaptic Transmission of the Nucleus of Solitary Tract Was Potentiated by Chronic Myocardial Infarction in Rats
Feng, Ban; Zhang, Zi-Nan; Lei, Jie; Li, Yun-Qing; Du, Jian-Qing; Chen, Tao
Angina pectoris is a common clinical symptom that often results from myocardial infarction. One typical characteristic of angina pectoris is that the pain does not match the severity of the myocardial ischemia. One possible explanation is that the intensity of cardiac nociceptive information could be dynamically regulated by certain brain areas. As an important nucleus for processing cardiac nociception, the nucleus of the solitary tract (NTS) has been studied to some extent. However, until now, the morphological and functional involvement of the NTS in chronic myocardial infarction (CMI) has remained unknown. In the present study, by exploring left anterior descending coronary artery ligation surgery, we found that the number of synaptophysin-immunoreactive puncta and Fos-immunoreactive neurons in the rat NTS two weeks after ligation surgery increased significantly. Excitatory pre- and postsynaptic transmission was potentiated. A bath application of a Ca2+ channel inhibitor GABApentin and Ca2+ permeable AMPA receptor antagonist NASPM could reverse the potentiated pre- and postsynaptic transmission, respectively. Meanwhile, rats with CMI showed significantly increased visceral pain behaviors. Microinjection of GABApentin or NASPM into the NTS decreased the CMI-induced visceral pain behaviors. In sum, our results suggest that the NTS is an important area for the process of cardiac afference in chronic myocardial infarction condition. PMID:25756354
Deletion of the amyloid precursor-like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus.
Vnencak, Matej; Paul, Mandy H; Hick, Meike; Schwarzacher, Stephan W; Del Turco, Domenico; Müller, Ulrike C; Deller, Thomas; Jedlicka, Peter
Amyloid precursor-like protein 1 (APLP1) is a transmembrane synaptic protein belonging to the amyloid precursor protein (APP) gene family. Although the role of this gene family-in particular of APP-has been intensely studied in the context of Alzheimer's disease, the physiological roles of its family members remain poorly understood. In particular, the function of APLP1, which is predominantly expressed in the nervous system, has remained enigmatic. Since APP has been implicated in synaptic plasticity, we wondered whether APLP1 could play a similar role. First, using in situ hybridization and laser microdissection combined with reverse transcription-quantitative polymerase chain reaction (PCR) we observed that Aplp1 mRNA is highly expressed in dentate granule cells. Having this examined, we studied synaptic plasticity at the perforant path-granule cell synapses in the dentate gyrus of APLP1-deficient mice in vivo. Analysis of field excitatory postsynaptic potentials evoked by stimulation of perforant path fibers revealed increased excitatory transmission in APLP1-deficient mice. Moreover, we observed decreased paired-pulse inhibition of population spikes indicating a decrease in network inhibition upon deletion of APLP1. In contrast, short-term presynaptic plasticity (STP) as well as long-term synaptic plasticity (LTP) was unchanged in the absence of APLP1. Based on these results we conclude that APLP1 deficiency on its own does not lead to defects in synaptic plasticity, but affects synaptic transmission and network inhibition in the dentate gyrus. J. Comp. Neurol. 523:1717-1729, 2015. © 2015 Wiley Periodicals, Inc. PMID:25728909
A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus.
Ceolin, Laura; Bortolotto, Zuner A; Bannister, Neil; Collingridge, Graham L; Lodge, David; Volianskis, Arturas
Perampanel is a non-competitive AMPA receptor antagonist that is under development as an anti-epileptic therapy. Although it is known to reduce calcium flux mediated by AMPA receptors in cultured cortical neurons, there are no studies of its selectivity in synaptic transmission in more intact systems. In the present study using hippocampal slices, perampanel (0.01-10 ?M) has been tested on pharmacologically isolated synaptic responses mediated by AMPA, NMDA or kainate receptors. Perampanel reduced AMPA receptor-mediated excitatory postsynaptic field potentials (f-EPSPs) with an IC(50) of 0.23 ?M and a full block at 3 ?M. This compares with an IC(50) of 7.8 ?M for GYKI52466 on these responses. By contrast, perampanel at 10 ?M had no effect on responses mediated by NMDA or kainate receptors, which were completely blocked by 30 ?M D-AP5 and 10 ?M NBQX respectively. The concentrations of perampanel required to reduce AMPA receptor-mediated responses are not dissimilar to those in plasma following anti-convulsant doses and are consistent with AMPA receptor antagonism being its primary mode of action. PMID:22433907
Loss of Predominant Shank3 Isoforms Results in Hippocampus-Dependent Impairments in Behavior and Synaptic Transmission
Kouser, Mehreen; Speed, Haley E.; Dewey, Colleen M.; Reimers, Jeremy M.; Widman, Allie J.; Gupta, Natasha; Liu, Shunan; Jaramillo, Thomas C.; Bangash, Muhammad; Xiao, Bo; Worley, Paul F.
The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory. PMID:24259569
Effects of the anaesthetic 2,6-diisopropylphenol on synaptic transmission in the rat olfactory cortex slice.
Collins, G. G.
1. The effects of the general anaesthetic 2,6-diisopropylphenol (DIP) on synaptic transmission and the actions of amino acid transmitter candidates have been investigated in rat olfactory cortex slices. 2. On electrical stimulation of the lateral olfactory tract (LOT), DIP (20 to 200 microM) increased the area of those surface field potentials which reflect gamma-aminobutyric acid (GABA)-mediated transmission in a concentration-dependent manner in 6 out of 12 slices. In a series of conditioning experiments, DIP (50 microM) also potentiated GABA-mediated pre- and post-synaptic inhibition. 3. Perfusion of slices with DIP (50 microM) potentiated the reduction in the excitability of the terminals of the LOT produced by exogenous GABA in a picrotoxin-sensitive manner. 4. DIP (50 microM) markedly potentiated the surface depolarizations evoked by GABA, muscimol and 3-aminopropanesulphonic acid. The effect on the response to 3-aminopropanesulphonic acid was observed over a concentration range of DIP of 6.25 to 50 microM and was not blocked by the benzodiazepine receptor antagonist Ro 15-1788. 5. In slices in which GABA-mediated transmission was abolished by picrotoxin (25 microM), DIP (50 microM) had no significant effect on monosynaptically-evoked excitatory transmission but depressed the areas of those field potentials which reflect di-/polysynaptic excitations in a concentration-dependent manner (from between 1.6 and 6.25 to 50 microM). 6. In a series of conditioning experiments DIP (50 microM) abolished the increase in the excitability of the pyramidal cells evoked on stimulation of deep association fibres. 7. DIP (50 microM) had no significant effect on surface depolarizations evoked by N-methyl-D-aspartate, quisqualate and kainate or by the transmitter candidates L-glutamate and L-aspartate. 8. It is concluded that, at clinically relevant concentrations, DIP potentiates GABA-mediated transmission probably by an interaction with the GABA receptor complex and inhibits di-/polysynaptic excitations, possibly by inhibiting the release of excitatory transmitters. PMID:2850066
Effects of prenatal paraquat and mancozeb exposure on amino acid synaptic transmission in developing mouse cerebellar cortex.
Miranda-Contreras, Leticia; Dávila-Ovalles, Rosaura; Benítez-Díaz, Pedro; Peńa-Contreras, Zulma; Palacios-Prü, Ernesto
The goal of this study was to analyze the effects of prenatal exposure to the pesticides paraquat (PQ) and mancozeb (MZ) on the development of synaptic transmission in mouse cerebellar cortex. Pregnant NMRI mice were treated with either saline, 10 mg/kg PQ, 30 mg/kg MZ or the combination of PQ + MZ, between gestational days 12 (E12) and E20. Variation in the levels of amino acid neurotransmitters was determined by HPLC, between postnatal day 1 (P1) and P30. Motor coordination was assessed by locomotor activity evaluation of control and experimental pups at P14, P21 and P30. Significant reductions in the levels of excitatory neurotransmitters, aspartate and glutamate, were observed in PQ-, MZ- or combined PQ + MZ-exposed pups, with respect to control, during peak periods of excitatory innervation of Purkinje cells: between P2-P5 and P11-P15. However, at P30, lower aspartate contents, in contrast with increased glutamate levels, were detected in all experimental groups. During the first two postnatal weeks, delays in GABA and glycine ontogenesis were observed in PQ- and PQ + MZ-exposed pups, whereas notable decrements in GABA and glycine levels were seen in PQ + MZ-exposed animals. Decreased taurine contents were detected at P3 and P11 in PQ- and PQ + MZ-exposed mice. Pups in different experimental groups all showed hyperactivity at P14 and then exhibited reduced locomotor activity at P30. Taken together, our results indicate that prenatal exposure to either PQ or MZ or the combination of both could alter the chronology and magnitude of synaptic transmission in developing mouse cerebellar cortex. PMID:16198425
Synchronized GABAergic IPSPs recorded in the neocortex after blockade of synaptic transmission mediated by excitatory amino acids.
Aram, J A; Michelson, H B; Wong, R K
1. Intracellular and extracellular recordings were carried out in guinea pig neocortical slices to examine the effects of blockade of excitatory amino acid (EAA) synaptic transmission on population discharges elicited by 4-aminopyridine (4-AP; 50-100 microM). 2. After the introduction of 4-AP, two distinct types of rhythmic spontaneous field potentials were recorded in neocortical slices. Type I consisted of multiple spike discharges lasting 20-90 s. These events occurred at a frequency of 0.4-0.2/min. Type II were single field potential spikes (3-6 s in duration) occurring at a higher frequency (2-4/min). 3. Blockade of amino acid-mediated excitatory synaptic transmission with D-2-amino-5-phosphonovaleric acid (D-AP5; 10-30 microM) or 3-(2-carboxypiperazin-4-yl)propyl-l-phosphonic acid (CPP, 10 microM) and 6-cyano-7nitroquinoxaline-2,3-dione (CNQX; 10 microM) abolished the first type of 4-AP-induced field potential, whereas type II events persisted. 4. Type II field events, occurring in the presence of EAA blockers, were further characterized by paired recordings. Events recorded along an axis orthogonal to the pia surface occurred simultaneously without measurable delay. Recordings made along a plane parallel to the pia surface showed that type II discharges propagated over distances of greater than or equal to 3 mm at an estimated velocity of 7.5 mm/s. 5. Intracellular recordings show that during type II field discharges all cells exhibited phasic depolarizations or hyperpolarizations, depending on the resting membrane potential. When resting potentials were more depolarized than -68 mV, events became mostly hyperpolarizing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1678421
Enhanced GABAergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model
Takasu, Keiko; Ogawa, Koichi; Nakamura, Atsushi; Kanbara, Tomoe; Ono, Hiroko; Tomii, Takako; Morioka, Yasuhide; Hasegawa, Minoru; Shibasaki, Masahiro; Mori, Tomohisa; Suzuki, Tsutomu; Sakaguchi, Gaku
Background and Purpose We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain. Experimental Approach We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model. Key Results The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input–output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir3.1 channels. Conclusion and Implications Our results demonstrate that Kir3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir3.1 channel activation. PMID:25521524
Loss of neuronal GSK3? reduces dendritic spine stability and attenuates excitatory synaptic transmission via ?-catenin
Ochs, S M; Dorostkar, M M; Aramuni, G; Schön, C; Filser, S; Pöschl, J; Kremer, A; Van Leuven, F; Ovsepian, S V; Herms, J
Central nervous glycogen synthase kinase 3? (GSK3?) is implicated in a number of neuropsychiatric diseases, such as bipolar disorder, depression, schizophrenia, fragile X syndrome or anxiety disorder. Many drugs employed to treat these conditions inhibit GSK3? either directly or indirectly. We studied how conditional knockout of GSK3? affected structural synaptic plasticity. Deletion of the GSK3? gene in a subset of cortical and hippocampal neurons in adult mice led to reduced spine density. In vivo imaging revealed that this was caused by a loss of persistent spines, whereas stabilization of newly formed spines was reduced. In electrophysiological recordings, these structural alterations correlated with a considerable drop in the frequency and amplitude of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active ?-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3? knockout, suggesting that the effects of GSK3? knockout were mediated by the accumulation of ?-catenin. In summary, changes of dendritic spines, both in quantity and in morphology, are correlates of experience-dependent synaptic plasticity; thus, these results may help explain the mechanism of action of psychotropic drugs inhibiting GSK3?. PMID:24912492
Loss of neuronal GSK3? reduces dendritic spine stability and attenuates excitatory synaptic transmission via ?-catenin.
Ochs, S M; Dorostkar, M M; Aramuni, G; Schön, C; Filser, S; Pöschl, J; Kremer, A; Van Leuven, F; Ovsepian, S V; Herms, J
Central nervous glycogen synthase kinase 3? (GSK3?) is implicated in a number of neuropsychiatric diseases, such as bipolar disorder, depression, schizophrenia, fragile X syndrome or anxiety disorder. Many drugs employed to treat these conditions inhibit GSK3? either directly or indirectly. We studied how conditional knockout of GSK3? affected structural synaptic plasticity. Deletion of the GSK3? gene in a subset of cortical and hippocampal neurons in adult mice led to reduced spine density. In vivo imaging revealed that this was caused by a loss of persistent spines, whereas stabilization of newly formed spines was reduced. In electrophysiological recordings, these structural alterations correlated with a considerable drop in the frequency and amplitude of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active ?-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3? knockout, suggesting that the effects of GSK3? knockout were mediated by the accumulation of ?-catenin. In summary, changes of dendritic spines, both in quantity and in morphology, are correlates of experience-dependent synaptic plasticity; thus, these results may help explain the mechanism of action of psychotropic drugs inhibiting GSK3?. PMID:24912492
Modulation of transient receptor potential vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C
Cao, De-Shou; Yu, Shuang-Quan; Premkumar, Louis S
Background Transient receptor potential Vanilloid (TRPV) receptors are involved in nociception and are expressed predominantly in sensory neurons. TRPV1, a non-selective cation channel has been extensively studied and is responsible for inflammatory thermal hypersensitivity. In this study, the expression and function of TRPV4 have been characterized and compared with those of TRPV1. Results Immunohistochemical studies revealed that both TRPV1 and TRPV4 were co-expressed in dorsal root ganglion (DRG) neuronal cell bodies and in the central terminals of laminae I and II of the spinal dorsal horn (DH). In Ca2+ fluorescence imaging and whole-cell patch-clamp experiments, TRPV1- and TRPV4-mediated responses were observed in a population of the same DRG neurons. Sensitization of TRPV1 has been shown to be involved in inflammatory pain conditions. Incubation with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significant potentiation of TRPV4 currents in DRG neurons. In TRPV4 expressing HEK 293T cells, PDBu increased 4?-phorbol 12, 13-didecanoate (4?-PDD)-induced single-channel activity in cell-attached patches, which was abrogated by bisindolylmaleimide (BIM), a selective PKC inhibitor. TRPV4 is also expressed at the central terminals of sensory neurons. Activation of TRPV4 by 4?-PDD increased the frequency of miniature excitatory post synaptic currents (mEPSCs) in DRG-DH neuronal co-cultures. 4?-PDD-induced increase in the frequency of mEPSCs was further enhanced by PDBu. The expression of TRP channels has been shown in other areas of the CNS; application of 4?-PDD significantly increased the mEPSC frequency in cultured hippocampal neurons, which was further potentiated by PDBu, whereas, TRPV1 agonist capsaicin did not modulate synaptic transmission. Conclusion These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception. PMID:19208258
Kv1 channels and neural processing in vestibular calyx afferents
Meredith, Frances L.; Kirk, Matthew E.; Rennie, Katherine J.
Potassium-selective ion channels are important for accurate transmission of signals from auditory and vestibular sensory end organs to their targets in the central nervous system. During different gravity conditions, astronauts experience altered input signals from the peripheral vestibular system resulting in sensorimotor dysfunction. Adaptation to altered sensory input occurs, but it is not explicitly known whether this involves synaptic modifications within the vestibular epithelia. Future investigations of such potential plasticity require a better understanding of the electrophysiological mechanisms underlying the known heterogeneity of afferent discharge under normal conditions. This study advances this understanding by examining the role of the Kv1 potassium channel family in mediating action potentials in specialized vestibular afferent calyx endings in the gerbil crista and utricle. Pharmacological agents selective for different sub-types of Kv1 channels were tested on membrane responses in whole cell recordings in the crista. Kv1 channels sensitive to ?-dendrotoxin and dendrotoxin-K were found to prevail in the central regions, whereas K+ channels sensitive to margatoxin, which blocks Kv1.3 and 1.6 channels, were more prominent in peripheral regions. Margatoxin-sensitive currents showed voltage-dependent inactivation. Dendrotoxin-sensitive currents showed no inactivation and dampened excitability in calyces in central neuroepithelial regions. The differential distribution of Kv1 potassium channels in vestibular afferents supports their importance in accurately relaying gravitational and head movement signals through specialized lines to the central nervous system. Pharmacological modulation of specific groups of K+ channels could help alleviate vestibular dysfunction on earth and in space.
In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome
Wang, Tiantian; de Kok, Laura; Willemsen, Rob; Elgersma, Ype; Borst, J. Gerard G.
Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.
Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors.
Booker, Sam A; Pires, Nuno; Cobb, Stuart; Soares-da-Silva, Patrício; Vida, Imre
This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED50 value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A1 receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation. PMID:25656478
Enhanced Synaptic Inhibition Disrupts the Efferent Code of Cerebellar Purkinje Neurons in Leaner Ca v 2.1 Ca 2+ Channel Mutant Mice
Saak V. Ovsepian; David D. Friel
Cerebellar Purkinje cells (PCs) encode afferent information in the rate and temporal structure of their spike trains. Both\\u000a spontaneous firing in these neurons and its modulation by synaptic inputs depend on Ca2+ current carried by Cav2.1 (P\\/Q) type channels. Previous studies have described how loss-of-function Cav2.1 mutations affect intrinsic excitability and excitatory transmission in PCs. This study examines the effects
Cells in Laminae III and IV of the Rat Spinal Cord that Possess the Neurokinin1 Receptor and Have Dorsally Directed Dendrites Receive a Major Synaptic Input from Tachykinin-Containing Primary Afferents
Magda Naim; Rosemary C. Spike; Christine Watt; Safa A. S. Shehab; Andrew J. Todd
Many neurons with cell bodies in laminae III or IV of the spinal dorsal horn possess the neurokinin 1 receptor and have dorsal dendrites that arborize in the superficial dorsal horn. We have performed a confocal microscopic study to determine whether these cells receive inputs from substance P-containing primary afferents. All neurons of this type received contacts from substance P-immunoreactive
Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice
Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M.J.M.; Pietrobon, Daniela
Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca2+] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory–inhibitory balance in FHM1. PMID:24907493
[Facilitation of synaptic transmission and connections of entorhinal-hippocampal pathway by 5-HT2C receptor subtype: multi-electrode array recordings].
Xu, Yan; Jin, Jian-Hui; Wang, Yan; Wang, Rui-Rui; Li, Zhen; Chen, Jun
Using 64-channels (8 × 8) multi-electrode array technique (MED-64 system), the modulatory actions of 5-hydroxytryptamine (5-HT) 2C receptor subtype on the entorhinal (EC)-hippocampal synaptic transmission and connections were studied. One of freshly dissociated acute hippocampal slices of rats which was placed on the MED-64 probe, was subject to constant perfusion with oxygenated artificial cerebrospinal fluid (ACSF, 95% O2 and 5% CO2). Two hours after ACSF incubation, simultaneous multi-site electrophysiological recordings were performed. One electrode was selected to be used for perforant path (PP) stimulation, and the remaining 63 electrodes were used for recordings of network field excitatory postsynaptic potentials (fEPSPs) within both CA1 and dentate gyrus (DG) that have been previously proved to be mediated by glutamate non-NMDA receptors. After stability of network fEPSPs was achieved, (±)-1(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, an agonist of 5-HT2C receptor subtype), or SB242084 (6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride hydrate) (a selective antagonist of 5-HT2C receptor subtype) was applied for 10 min perfusion, respectively. Two-dimensional current source density (2D-CSD) analysis was also transformed by bilinear interpolation at each point of the 64 electrodes for spatial imaging of the fEPSP network responses. Based upon the polarities of fEPSP and 2D-CSD imaging, it was clearly shown that synaptic activations were evoked to occur within the molecular layer of DG and pyramidal cell layer of CA1 by the PP stimulation in which negative-going field potentials and current sink (blue) could be recorded. While, positive-going field potentials and current source (yellow) were mainly localized within the granule cell layer and hilus of DG and alveus of CA1, reflecting spread of electrical signals derived from depolarized region toward CA3 area or subiculum and fimbria along the axons. Perfusion of the hippocampal slices with DOI resulted in a significant enlargement of synaptic connection size at network level and enhancement of synaptic efficacy. However, on the contrary, perfusion with SB242084 produced reversal effect with either reduction in synaptic network size or decreased magnitude of fEPSPs (amplitude and slope) in the CA1 and DG. These results suggest that endogenous 5-HT causes facilitation of EC-CA1 and EC-DG synaptic transmission and connections via acting on 5-HT2C receptor subtype, leading to gain in synaptic transmission and enlargement of synaptic connections. PMID:22717628
Neuropeptide S-Mediated Facilitation of Synaptic Transmission Enforces Subthreshold Theta Oscillations within the Lateral Amygdala
Meis, Susanne; Stork, Oliver; Munsch, Thomas
The neuropeptide S (NPS) receptor system modulates neuronal circuit activity in the amygdala in conjunction with fear, anxiety and the expression and extinction of previously acquired fear memories. Using in vitro brain slice preparations of transgenic GAD67-GFP (?neo) mice, we investigated the effects of NPS on neural activity in the lateral amygdala as a key region for the formation and extinction of fear memories. We are able to demonstrate that NPS augments excitatory glutamatergic synaptic input onto both projection neurons and interneurons of the lateral amygdala, resulting in enhanced spike activity of both types of cells. These effects were at least in part mediated by presynaptic mechanisms. In turn, inhibition of projection neurons by local interneurons was augmented by NPS, and subthreshold oscillations were strengthened, leading to their shift into the theta frequency range. These data suggest that the multifaceted effects of NPS on amygdaloid circuitry may shape behavior-related network activity patterns in the amygdala and reflect the peptide's potent activity in various forms of affective behavior and emotional memory. PMID:21437203
Cholinergic efferent synaptic transmission regulates the maturation of auditory hair cell ribbon synapses
Johnson, Stuart L.; Wedemeyer, Carolina; Vetter, Douglas E.; Adachi, Roberto; Holley, Matthew C.; Elgoyhen, Ana Belén; Marcotti, Walter
Spontaneous electrical activity generated by developing sensory cells and neurons is crucial for the maturation of neural circuits. The full maturation of mammalian auditory inner hair cells (IHCs) depends on patterns of spontaneous action potentials during a 'critical period' of development. The intrinsic spiking activity of IHCs can be modulated by inhibitory input from cholinergic efferent fibres descending from the brainstem, which transiently innervate immature IHCs. However, it remains unknown whether this transient efferent input to developing IHCs is required for their functional maturation. We used a mouse model that lacks the ?9-nicotinic acetylcholine receptor subunit (?9nAChR) in IHCs and another lacking synaptotagmin-2 in the efferent terminals to remove or reduce efferent input to IHCs, respectively. We found that the efferent system is required for the developmental linearization of the Ca2+-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their general cell development. This provides the first direct evidence that the efferent system, by modulating IHC electrical activity, is required for the maturation of the IHC synaptic machinery. The central control of sensory cell development is unique among sensory systems. PMID:24350389
Glycinergic synaptic transmission in the cochlear nucleus of mice with normal hearing and age-related hearing loss
Xie (???), Ruili
The principal inhibitory neurotransmitter in the mammalian cochlear nucleus (CN) is glycine. During age-related hearing loss (AHL), glycinergic inhibition becomes weaker in CN. However, it is unclear what aspects of glycinergic transmission are responsible for weaker inhibition with AHL. We examined glycinergic transmission onto bushy cells of the anteroventral CN in normal-hearing CBA/CaJ mice and in DBA/2J mice, a strain that exhibits an early onset AHL. Glycinergic synaptic transmission was examined in brain slices of mice at 10–15 postnatal days old, 20–35 days old, and at 6–7 mo old. Spontaneous inhibitory postsynaptic current (sIPSC) event frequency and amplitude were the same among all three ages in both strains of mice. However, the amplitudes of IPSCs evoked (eIPSC) from stimulating the dorsal CN were smaller, and the failure rate was higher, with increasing age due to decreased quantal content in both mouse strains, independent of hearing status. The coefficient of variation of the eIPSC amplitude also increased with age. The decay time constant (?) of sIPSCs and eIPSCs were constant in CBA/CaJ mice at all ages, but were significantly slower in DBA/2J mice at postnatal days 20–35, following the onset of AHL, and not at earlier or later ages. Our results suggest that glycinergic inhibition at the synapses onto bushy cells becomes weaker and less reliable with age through changes in release. However, the hearing loss in DBA/2J mice is accompanied by a transiently enhanced inhibition, which could disrupt the balance of excitation and inhibition. PMID:23904491
Convergence of cranial visceral afferents within the solitary tract nucleus
McDougall, Stuart J.; Peters, James H.; Andresen, Michael C.
Primary afferent axons within the solitary tract (ST) relay homeostatic information via glutamatergic synapses directly to 2nd order neurons within the nucleus of the solitary tract (NTS). These primary afferents arise from multiple organ systems and relay multiple sensory modalities. How this compact network organizes the flow of primary afferent information will shape central homeostatic control. To assess afferent convergence and divergence, we recorded ST-evoked synaptic responses in pairs of medial NTS neurons in horizontal brainstem slices. ST shocks activated EPSCs along monosynaptic or polysynaptic pathways. Gradations in shock intensity discriminated multiple inputs and stimulus recruitment profiles indicated that each EPSC was unitary. In 24 pairs, 75% were 2nd order neurons with 64% receiving one direct ST input with the remainder receiving additional convergent ST afferent inputs (22% two; 14% three monosynaptic ST-EPSCs). Some (34%) 2nd order neurons received polysynaptic EPSCs. Neurons receiving only higher order inputs were uncommon (13%). Most ST-EPSCs were completely independent, but four EPSCs of a total of 81 had equal thresholds, highly correlated latencies and synchronized synaptic failures consistent with divergence from a single source ST axon or from a common interneuron producing a pair of polysynaptic EPSCs. We conclude that ST afferent inputs are remarkably independent with little evidence of substantial shared information. Individual cells receive highly focused information from the viscera. Thus, afferent excitation of 2nd order NTS neurons is generally dominated by single visceral afferents and therefore focused on a single afferent modality and/or organ region. PMID:19828803
The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization
Amy Arai; Gary Lynch
Relationships between the kinetic properties of AMPA receptors and the decay phase of fast excitatory transmission were investigated using modulatory drugs. The benzothiadiazide compound cyclothiazide blocked receptor desensitization in patches excised from hippocampus but had only a weak influence on receptor deactivation, i.e., on the decay of responses produced by a 1-ms pulse of glutamate. The ampakine drug CX516 (BDP-12)
Eugenol depresses synaptic transmission but does not prevent the induction of long-term potentiation in the CA1 region of rat hippocampal slices.
Ardjmand, A; Fathollahi, Y; Sayyah, M; Kamalinejad, M; Omrani, A
Using field potential recording in the CA1 region of the rat hippocampal slices, the effects of eugenol on synaptic transmission and long-term potentiation (LTP) were investigated. Population spikes (PS) were recorded in the stratum pyramidal following stimulation of stratum fibers. To induce LTP, eight episodes of theta pattern primed-bursts (PBs) were delivered. Eugenol decreased the amplitude of PS in a concentration-dependent manner. The effect was fast and completely reversible. Eugenol had no effect on PBs-induced LTP of PS. It is concluded that while eugenol depresses synaptic transmission it does not affect the ability of CA1 synapses for tetanus-induced LTP and plasticity. PMID:16428020
Effects of ketamine on synaptic transmission and long-term potentiation in layer II\\/III of rat visual cortex in vitro
Mahmoud Salami; Yaghoub Fathollahi; Hossein Esteky; Fereshteh Motamedi; Nafiseh Atapour
The effects of ketamine, which has NMDA receptor antagonist properties, on synaptic transmission and long-term potentiation in layer II\\/III of adult rat visual cortex were examined in vitro. Field potentials were recorded in layer II\\/III following layer IV stimulation. Primed-burst stimulation was used for induction of long-term potentiation. Stimulation of layer IV resulted in a two-component response in layer II\\/III,
Deprenyl blocks the aglycemia-induced depression of the synaptic transmission but not the ischemia-induced depression in neonatal rat spinal cord in vitro
Archana Jha; Shyamal Das Gupta; Shripad B. Deshpande
The protective action of R-(?)-deprenyl against the aglycemia (glucose-free) and the ischemia (glucose-free and O2-free)-induced changes in the synaptic transmission was investigated. The in vitro "glucose-free and O2-free" condition mimics in vivo ischemia where there is a deficiency of O2 and energy substrate, hence the term ischemia was used. The monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials were elicited
Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression
H. Norman; J. Nordquist; P. Andersson; T. Ansved; X. Tang; B. Dworkin; L. Larsson
To analyse mechanisms of muscle wasting in intensive care unit patients, we developed an experimental model where rats were pharmacologically paralysed by post-synaptic block of neuromuscular transmission (NMB) and mechanically ventilated for 9±2 days. Specific interest was focused on the effects on protein and mRNA expression of sarcomeric proteins, i.e., myosin heavy chain (MyHC), actin, myosin-binding protein C (MyBP-C) and myosin-binding
Recruitment of New Sites of Synaptic Transmission During the cAMP-Dependent Late Phase of LTP at CA3–CA1 Synapses in the Hippocampus
Vadim Y. Bolshakov; Hava Golan; Eric R. Kandel; Steven A. Siegelbaum
Long-term potentiation at CA3–CA1 hippocampal synapses exhibits an early phase and a late phase, which can be distinguished by their underlying molecular mechanisms. Unlike the early phase, the late phase is dependent on both cAMP and protein synthesis. Quantal analysis of unitary synaptic transmission between a single presynaptic CA3 neuron and a single postsynaptic CA1 neuron suggests that, under certain
Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures
Weston, Matthew C.; Chen, Hongmei; Swann, John W.
The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism. PMID:24574959
Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
Fraser, M M; Bayazitov, I T; Zakharenko, S S; Baker, S J
The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function. PMID:18082964
Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming
Frederique Varoqueaux; Albrecht Sigler; Jeong-Seop Rhee; Nils Brose; Carsten Enk; Kerstin Reim; Christian Rosenmund
Synaptic vesicles must be primed to fusion competence before they can fuse with the plasma membrane in response to increased intracellular Ca2+ levels. The presynaptic active zone protein Munc13-1 is essential for priming of glutamatergic synaptic vesicles in hippocampal neurons. However, a small subpopulation of synapses in any given glutamatergic nerve cell as well as all -aminobutyratergic (GABAergic) synapses are
Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex.
Kiritoshi, Takaki; Neugebauer, Volker
The medial prefrontal cortex (mPFC) serves executive control functions that are impaired in neuropsychiatric disorders and pain. Therefore, restoring normal synaptic transmission and output is a desirable goal. Group II metabotropic glutamate receptors mGluR2 and mGluR3 are highly expressed in the mPFC, modulate synaptic transmission, and have been targeted for neuropsychiatric disorders. Their pain-related modulatory effects in the mPFC remain to be determined. Here we evaluated their ability to restore pyramidal output in an arthritis pain model. Whole-cell patch-clamp recordings of layer V mPFC pyramidal cells show that a selective group II mGluR agonist (LY379268) decreased synaptically evoked spiking in brain slices from normal and arthritic rats. Effects were concentration-dependent and reversed by a selective antagonist (LY341495). LY379268 decreased monosynaptic excitatory postsynaptic currents (EPSCs) and glutamate-driven inhibitory postsynaptic currents (IPSCs) in the pain model. Effects on EPSCs preceded those on IPSCs and could explain the overall inhibitory effect on pyramidal output. LY379268 decreased frequency, but not amplitude, of miniature EPSCs without affecting miniature IPSCs. LY341495 alone increased synaptically evoked spiking under normal conditions and in the pain model. In conclusion, group II mGluRs act on glutamatergic synapses to inhibit direct excitatory transmission and feedforward inhibition onto pyramidal cells. Their net effect is decreased pyramidal cell output. Facilitatory effects of a group II antagonist suggest the system may be tonically active to control pyramidal output. Failure to release the inhibitory tone and enhance mPFC output could be a mechanism for the development or persistence of a disease state such as pain. PMID:25912637
Metaplasticity: the plasticity of synaptic plasticity
Wickliffe C. Abraham; Mark F. Bear
In thi paper, we review experimental evidence for a novel form of persistent synaptic plasticity we call metaplasticity. Metaplasticity is induced by synaptic or cellular activity, but it is not necessarilly expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifest as a change in the ability to induce subsequent synaptic plasticity such as long-term
GABAB receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneurons
Lei, Saobo; McBain, Chris J
Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABAB receptor-mediated responses at both synapse types. Postsynaptic GABAB receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (?P30) suggesting developmental regulation. In young animals, the GABAB receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd2+, implicating presynaptic voltage-gated Ca2+ channels as a target for baclofen modulation. In contrast, although Cd2+ prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca2+ channels contributed equally to GABAB receptor-mediated inhibition of EPSCs, more P/Q-type Ca2+ channels were involved in GABAB receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABAB receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types. PMID:12527730
Developmental profiles of glutamate receptors and synaptic transmission at a single synapse in the mouse auditory brainstem
Joshi, Indu; Wang, Lu-Yang
Using whole-cell recordings from presynaptic terminals and postsynaptic principal neurons in the mouse medial nucleus of the trapezoid body (MNTB), we have characterized properties of the calyx of Held synapse during the first three postnatal weeks. We observed that evoked excitatory postsynaptic currents (EPSCs) mediated by NMDA receptors (NMDAR) increased until postnatal day 11/12 (P11/12) after which they declined to very low or undetectable levels at P16. Meanwhile, EPSCs mediated by AMPA receptors (AMPAR) showed an approximate three-fold increase in amplitude. These changes were paralleled by NMDAR and AMPAR currents evoked by exogenous NMDA and kainate to MNTB neurons except that whole-cell kainate currents remained constant after P7/8 while AMPAR-EPSCs continued to increase. We found that the decay time constant ? for NMDAR-EPSCs and AMPAR-EPSCs declined by about 30 % and 70 %, respectively. Analyses of NMDAR-EPSCs with subunit-specific pharmacological agents including ifenprodil, N,N,N?,N?-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), zinc and Mg2+ revealed subtle developmental changes in subunit composition. As maturation progressed, this synapse displayed a reduction in the number of presynaptic spike failures and the extent of synaptic depression in response to trains of stimuli (50–300 Hz) while the recovery rate from depression accelerated. These results demonstrate profound changes in the size and kinetics of postsynaptic glutamate receptors and in the spike-firing capability of presynaptic terminals at the calyx of Held-MNTB synapse during early development. We suggest that these concurrent presynaptic and postsynaptic adaptations represent important steps for synapse consolidation and refinement and ultimately for the development of fast high-fidelity transmission at this synapse. PMID:11986375
Modulation of abnormal synaptic transmission in hippocampal CA3 neurons of spontaneously epileptic rats (SERs) by levetiracetam.
Hanaya, Ryosuke; Kiura, Yoshihiro; Serikawa, Tadao; Kurisu, Kaoru; Arita, Kazunori; Sasa, Masashi
Levetiracetam (LEV) inhibits partial refractory epilepsy in human, and both convulsive and absence-like seizures in the spontaneously epileptic rat (SER). Two-thirds of hippocampal CA3 neurons in SER show a long-lasting depolarization shift, with accompanying repetitive firing upon mossy fiber stimulation. This abnormal excitability is probably attributable to abnormalities in the L-type Ca(2+) channels. We performed electrophysiological studies to elucidate the mechanism underlying the antiepileptic effects of LEV via intracellular recording from the hippocampal CA3 neurons in slice preparations of SER and non-epileptic Wistar rats. LEV (100 ?M) inhibited the depolarization shift with repetitive firing by mossy fiber stimulation (MFS), without affecting the first spike in SER CA3 neurons. At a higher dose (1mM), LEV suppressed the first spike in all SER neurons (including the CA3 neurons which showed only a single action potential by MFS), while the single action potential of Wistar rat CA3 neurons remained unaffected. SER CA3 neurons with MFS-induced abnormal firing exhibited a higher number of repetitive spikes when a depolarization pulse was applied in the SER CA3 neurons. LEV (100 ?M, 1mM) reduced the repetitive firing induced by a depolarization pulse applied without affecting Ca(2+) spike in SER neurons. LEV is known not to bind glutamate and gamma-aminobutyric acid (GABA) receptors. These findings suggest that the therapeutic concentration of LEV inhibits abnormal firing of the CA3 neurons by modulating abnormal synaptic transmission and abnormal Na(+) channels in SER. PMID:21968023
Excitatory and inhibitory synaptic transmission is differentially influenced by two ortho-substituted polychlorinated biphenyls in the hippocampal slice preparation
Kim, Authors: Kyung Ho; Inan, Salim Yalcin; Berman, Robert F.; Pessah, Isaac N.
Exposure to polychlorinated biphenyls impairs cognition and behavior in 'children. Two environmental PCBs 2,2?3,3?4,4?5-heptachlorobiphenyl (PCB170) and 2,2?3,5?6-pentachlorobiphenyl (PCB95) were examined in vitro for influences on synaptic transmission in rat hippocampal slices. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region using a multi-electrode array. Perfusion with PCB170 (10 nM) had no effect on fEPSP slope relative to baseline period, whereas (100 nM) initially enhanced then depressed fEPSP slope. Perfusion of PCB95 (10 or 100 nM) persistently enhanced fEPSP slope >200%, an effect that could be inhibited by dantrolene, a drug that attenuates ryanodine receptor signaling. Perfusion with picrotoxin (PTX) to block GABA neurotransmission resulted in a modest increase in fEPSP slope, whereas PTX+PCB170 (1–100 nM) persistently enhanced fEPSP slope in a dose dependent manner. fEPSP slope reached >250% of baseline period in the presence of PTX+100 nM PCB170, conditions that evoked marked epileptiform after-potential discharges. PCB95 and PCB170 were found to differentially influence the Ca2+-dependence of [3H]ryanodine-binding to hippocampal ryanodine receptors. Non-coplanar PCB congeners can differentially alter neurotransmission in a manner suggesting they can elicit imbalances between inhibitory and excitatory circuits within the hippocampus. Differential sensitization of ryanodine receptors by Ca2+ appears to mediate, at least in part, hippocampal excitotoxicity by non-coplanar PCBs. PMID:19289137
Central dysmyelination reduces the temporal fidelity of synaptic transmission and the reliability of postsynaptic firing during high-frequency stimulation
Kim, Sei Eun; Turkington, Karl; Kushmerick, Christopher
Auditory brain stem circuits rely on fast, precise, and reliable neurotransmission to process auditory information. To determine the fundamental role of myelination in auditory brain stem function, we examined the evoked auditory brain stem response (ABR) from the Long Evans shaker (LES) rat, which lacks myelin due to a genetic deletion of myelin basic protein. In control rats, the ABR evoked by a click consisted of five well-defined waves (denoted waves I–V). In LES rats, waves I, IV, and V were present, but waves II and III were undetectable, indicating disrupted function in the earliest stages of central nervous system auditory processing. In addition, the developmental shortening of the interval between waves I and IV that normally occurs in control rats was arrested and resulted in a significant increase in the central conduction time in LES rats. In brain stem slices, action potential transmission between the calyx of Held terminals and the medial nucleus of the trapezoid body (MNTB) neurons was delayed and less reliable in LES rats, although the resting potential, threshold, input resistance, and length of the axon initial segment of the postsynaptic MNTB neurons were normal. The amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) and the degree of synaptic depression during high-frequency stimulation were not different between LES rats and controls, but LES rats exhibited a marked slow component to the EPSC decay and a much higher rate of presynaptic failures. Together, these results indicate that loss of myelin disrupts brain stem auditory processing, increasing central conduction time and reducing the reliability of neurotransmission. PMID:23843435
Dendritic HCN channels shape excitatory postsynaptic potentials at the inner hair cell afferent synapse in the mammalian cochlea.
Yi, Eunyoung; Roux, Isabelle; Glowatzki, Elisabeth
Synaptic transmission at the inner hair cell (IHC) afferent synapse, the first synapse in the auditory pathway, is specialized for rapid and reliable signaling. Here we investigated the properties of a hyperpolarization-activated current (I(h)), expressed in the afferent dendrite of auditory nerve fibers, and its role in shaping postsynaptic activity. We used whole cell patch-clamp recordings from afferent dendrites directly where they contact the IHC in excised postnatal rat cochlear turns. Excitatory postsynaptic potentials (EPSPs) of variable amplitude (1-35 mV) were found with 10-90% rise times of about 1 ms and time constants of decay of about 5 ms at room temperature. Current-voltage relations recorded in afferent dendrites revealed I(h). The pharmacological profile and reversal potential (-45 mV) indicated that I(h) is mediated by hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels. The HCN channel subunits HCN1, HCN2, and HCN4 were found to be expressed in afferent dendrites using immunolabeling. Raising intracellular cAMP levels sped up the activation kinetics, increased the magnitude of I(h) and shifted the half activation voltage (V(half)) to more positive values (-104 +/- 3 to -91 +/- 2 mV). Blocking I(h) with 50 microM ZD7288 resulted in hyperpolarization of the resting membrane potential (approximately 4 mV) and slowing the decay of the EPSP by 47%, suggesting that I(h) is active at rest and shortens EPSPs, thereby potentially improving rapid and reliable signaling at this first synapse in the auditory pathway. PMID:20220080
VGLUT3-immunoreactive afferents of the lateral septum: ultrastructural evidence for a modulatory role of glutamate.
Riedel, Anett; Stöber, Franziska; Richter, Karin; Fischer, Klaus-Dieter; Miettinen, Riitta; Budinger, Eike
Through its extensive connections with various brain regions, the lateral septum (LS) participates in the processing of cognitive, emotional and autonomic information. It is decisively involved in the generation of behavioral responses according to environmental demands. Modulatory afferents reaching the LS from the brain stem (e.g. dopaminergic, serotonergic) play a role in the adjustment of these behavioral responses. Recently, a population of vesicular glutamate transporter 3-immunoreactive (VGLUT3-ir) fibers forming prominent pericellular basket-like structures (PBLS) was described in the rat LS. These VGLUT3-ir PBLS are distributed in a layer-like pattern, which is very typical for modulatory afferents of the LS. There is meanwhile broad evidence that glutamate can act as a modulatory or co-transmitter and that those neurons, which make use of this transmission mode, primarily express VGLUT3. Thus, the VGLUT3-ir fibers within the LS could also display features typical for non-canonical glutamatergic transmission. Employing pre-embedding electron microscopy for VGLUT3 in rats, we show now that the VGLUT3-ir fibers outlining LS neurons represent axonal terminals, which primarily form symmetric synapses with somata and proximal dendrites of their target neurons. Occasionally, we also found VGLUT3-ir terminals that make canonical asymmetric synapses on distal dendrites and spines. Thus, VGLUT3-ir boutons in the LS form two different, disproportionate, populations of synaptic contacts with their target neurons. The larger one of them is indicative of employing glutamate as a modulatory transmitter. PMID:22374223
Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an in vivo patch-clamp analysis of analgesic mechanisms
Funai, Yusuke; Pickering, Anthony Edward; Uta, Daisuke; Nishikawa, Kiyonobu; Mori, Takashi; Asada, Akira; Imoto, Keiji; Furue, Hidemasa
?2-adrenoceptors are widely distributed throughout the central nervous system (CNS) and the systemic administration of ?2-agonists such as dexmedetomidine produces clinically useful, centrally-mediated sedation and analgesia; however, these same actions also limit the utility of these agents (ie unwanted sedative actions). Despite a wealth of data on cellular and synaptic actions of ?2-agonists in vitro, it is not known which neuronal circuits are modulated in vivo to produce the analgesic effect. To address this issue, we made in vivo recordings of membrane currents and synaptic activities in superficial spinal dorsal horn neurons and examined their responses to systemic dexmedetomidine. We found that dexmedetomidine at doses that produce analgesia (<10 ?g/kg) enhanced inhibitory postsynaptic transmission within the superficial dorsal horn without altering excitatory synaptic transmission or evoking direct postsynaptic membrane currents. In contrast, higher doses of dexmedetomidine (>10 ?g/kg) induced outward currents by a direct postsynaptic action. The dexmedetomidine-mediated inhibitory postsynaptic current (IPSC) facilitation was not mimicked by spinal application of dexmedetomidine and was absent in spinalized rats, suggesting it acts at a supraspinal site. Further it was inhibited by spinal application of the ?1-antagonist prazosin. In the brain stem, low doses of systemic dexmedetomidine produced an excitation of locus coeruleus neurons. These results suggest that systemic ?2-adrenoceptor stimulation may facilitate inhibitory synaptic responses in the superficial dorsal horn to produce analgesia mediated by activation of the pontospinal noradrenergic inhibitory system. This novel mechanism may provide new targets for intervention perhaps allowing analgesic actions to be dissociated from excessive sedation. PMID:24355412
A fast synaptic potential mediated by NMDA and non-NMDA receptors.
Wolszon, L R; Pereda, A E; Faber, D S
A fast synaptic potential mediated by NMDA and non-NMDA receptors. J. Neurophysiol. 78: 2693-2706, 1997. Excitatory synaptic transmission in the CNS often is mediated by two kinetically distinct glutamate receptor subtypes that frequently are colocalized, the N-methyl--aspartate (NMDA) and non-NMDA receptors. Their synaptic currents are typically very slow and very fast, respectively. We examined the pharmacological and physiological properties of chemical excitatory transmission at the mixed electrical and chemical synapses between auditory afferents and the goldfish Mauthner cell, in vivo. Previous physiological data have suggested the involvement of glutamate receptors in this fast excitatory postsynaptic potential (EPSP), the chemical component of which decays with a time constant of <2 ms. We demonstrate here that the pharmacological and voltage-dependent characteristics of the synaptic currents are consistent with glutamatergic transmission and that both NMDA and non-NMDA receptors are involved. The two components surprisingly exhibit quite similar kinetics even at resting potential, with the NMDA response being only slightly slower. Due to its fast kinetics and characteristic voltage dependence, NMDA receptor-mediated transmission at these first-order synapses contributes significantly to paired pulse and frequency-dependent facilitation of successive fast EPSPs during high-frequency repetitive firing, a presynaptic impulse pattern that induces activity-dependent homosynaptic changes in both electrical and chemical transmission. Thus NMDA receptor kinetics in this intact preparation are suited to its functional requirements, namely speed of information transmission and the ability to trigger changes in synaptic efficacy. PMID:9356419
Transmission to Interneurons Is via Slow Excitatory Synaptic Potentials Mediated by P2Y1 Receptors during Descending Inhibition in Guinea-Pig Ileum
Thornton, Peter D. J.; Gwynne, Rachel M.; McMillan, Darren J.; Bornstein, Joel C.
Background The nature of synaptic transmission at functionally distinct synapses in intestinal reflex pathways has not been fully identified. In this study, we investigated whether transmission between interneurons in the descending inhibitory pathway is mediated by a purine acting at P2Y receptors to produce slow excitatory synaptic potentials (EPSPs). Methodology/Principal findings Myenteric neurons from guinea-pig ileum in vitro were impaled with intracellular microelectrodes. Responses to distension 15 mm oral to the recording site, in a separately perfused stimulation chamber and to electrical stimulation of local nerve trunks were recorded. A subset of neurons, previously identified as nitric oxide synthase immunoreactive descending interneurons, responded to both stimuli with slow EPSPs that were reversibly abolished by a high concentration of PPADS (30 ?M, P2 receptor antagonist). When added to the central chamber of a three chambered organ bath, PPADS concentration-dependently depressed transmission through that chamber of descending inhibitory reflexes, measured as inhibitory junction potentials in the circular muscle of the anal chamber. Reflexes evoked by distension in the central chamber were unaffected. A similar depression of transmission was seen when the specific P2Y1 receptor antagonist MRS 2179 (10 ?M) was in the central chamber. Blocking either nicotinic receptors (hexamethonium 200 ?M) or 5-HT3 receptors (granisetron 1 ?M) together with P2 receptors had no greater effect than blocking P2 receptors alone. Conclusions/Significance Slow EPSPs mediated by P2Y1 receptors, play a primary role in transmission between descending interneurons of the inhibitory reflexes in the guinea-pig ileum. This is the first demonstration for a primary role of excitatory metabotropic receptors in physiological transmission at a functionally identified synapse. PMID:23382795
Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels.
Nishio, N; Taniguchi, W; Sugimura, Y K; Takiguchi, N; Yamanaka, M; Kiyoyuki, Yasukuni; Yamada, H; Miyazaki, N; Yoshida, M; Nakatsuka, T
Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. However, it is unclear how ROS affect synaptic transmission in the dorsal horn of the spinal cord. To clarify how ROS impact on synaptic transmission, we investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings. Administration of tert-butyl hydroperoxide (t-BOOH), an ROS donor, into the spinal cord markedly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in SG neurons. This t-BOOH-induced enhancement was not suppressed by the Na(+) channel blocker tetrodotoxin. However, in the presence of a non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, t-BOOH did not generate any sEPSCs. Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI. PMID:23707800
Introduction Synaptic transmission
Stoltz, Brian M.
"Cys Loop" Superfamily of Ligand-Gated Ion Channels The ACh receptor also responds to nicotine, and so+ N CH3 H Serotonin (5-HT) N H NH3 + HO GABA + H3N CO2 Receptors for: Glycine + H3N CO2 #12 the chemical level, the key players include integral membrane proteins that control signaling Ligand-Gated Ion
Visceral afferents and metabolic function
A. Niijima
Summary The effect of glucose, 2 DG, CCK and serotonin on the firing rate of the vagal hepatic afferents and vagal pancreatic afferents\\u000a was studied in rabbits, guinea pigs and rats. The hepatic and pancreatic afferents showed a decrease in activity following\\u000a administration of glucose and an increase in activity after the injection of 2 DG. These afferent elements may have
Synaptic excitation produces a long-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells
M. Kano; U. Rexhausen; J. Dreessen; A. Konnerth
PERSISTENT changes in synaptic efficacy are thought to underlie the formation of learning and memory in the brain1. High-frequency activation of an afferent excitatory fibre system can induce long-term potentiation2,3, and conjunctive activation of two distinct excitatory synaptic inputs to the cerebellar Purkinje cells can lead to long-term depression of the synaptic activity of one of the inputs4. Here we
Comparison of the effects of neurokinin-3 receptor blockade on two forms of slow synaptic transmission in myenteric AH neurons.
Alex, G; Kunze, W A; Furness, J B; Clerc, N
AH neurons are intrinsic sensory neurons of the intestine that exhibit two types of slow synaptic event: slow excitatory postsynaptic potentials which increase their excitability for about 2-4 min, and sustained slow postsynaptic excitation which can persist for several hours, and may be involved in long-term changes in the sensitivity of the intestine to sensory stimuli. The effects of the neurokinin-3 tachykinin receptor antagonist, SR142801, on these two types of synaptic event in AH neurons of the myenteric ganglia of guinea-pig small intestine were compared. Slow excitatory postsynaptic potentials were evoked by stimulation of synaptic inputs at 10-20 Hz for 1s, and sustained slow postsynaptic excitation was evoked by stimulation of inputs at 1Hz for 4 min. SR142801 (1microM) reduced the amplitude of the slow excitatory postsynaptic potential to 26% of control, and also reduced the increase in input resistance and the extent of anode break excitation associated with the slow excitatory postsynaptic potential. In contrast, SR142801 did not reduce the increase in excitability, the increase in input resistance or the depolarisation that occur during the sustained slow postsynaptic excitation. SR142801 did not change the resting membrane potential or the resting input resistance. We conclude that tachykinins, acting through neurokinin-3 receptors, are involved in the generation of the slow excitatory postsynaptic potential, but not in the sustained slow postsynaptic excitation, and that the release of transmitters from synaptic inputs to AH neurons is frequency coded. PMID:11311548
Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex
Glovaci, Iulia; Chapman, C. Andrew
The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent upon both DAG and enhanced intracellular Ca2+. These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine. PMID:26133167
Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices.
Lindquist, B E; Shuttleworth, C W
Spreading depolarization (SD) is a slowly propagating, coordinated depolarization of brain tissue, which is followed by a transient (5-10min) depression of synaptic activity. The mechanisms for synaptic depression after SD are incompletely understood. We examined the relative contributions of action potential failure and adenosine receptor activation to the suppression of evoked synaptic activity in murine brain slices. Focal micro-injection of potassium chloride (KCl) was used to induce SD and synaptic potentials were evoked by electrical stimulation of Schaffer collateral inputs to hippocampal area Cornu Ammonis area 1 (CA1). SD was accompanied by loss of both presynaptic action potentials (as assessed from fiber volleys) and field excitatory postsynaptic potentials (fEPSPs). Fiber volleys recovered rapidly upon neutralization of the extracellular direct current (DC) potential, whereas fEPSPs underwent a secondary suppression phase lasting several minutes. Paired-pulse ratio was elevated during the secondary suppression period, consistent with a presynaptic mechanism of synaptic depression. A transient increase in extracellular adenosine concentration was detected during the period of secondary suppression. Antagonists of adenosine A1 receptors (8-cyclopentyl-1,3-dipropylxanthine [DPCPX] or 8-cyclopentyl-1,3-dimethylxanthine [8-CPT]) greatly accelerated fEPSP recovery and abolished increases in paired-pulse ratio normally observed after SD. The duration of fEPSP suppression was correlated with both the duration of the DC shift and the area of tissue depolarized, consistent with the model that adenosine accumulates in proportion to the metabolic burden of SD. These results suggest that in brain slices, the duration of the DC shift approximately defined the period of action potential failure, but the secondary depression of evoked responses was in large part due to endogenous adenosine accumulation after SD. PMID:22864185
Effect of low frequency stimulation of perforant path on kindling rate and synaptic transmission in the dentate gyrus during kindling acquisition in rats.
Mohammad-Zadeh, Mohammad; Mirnajafi-Zadeh, Javad; Fathollahi, Yaghoub; Javan, Mohammad; Ghorbani, Parviz; Sadegh, Mehdi; Noorbakhsh, Seyed Mohammad
Low frequency stimulation (LFS) has an inhibitory effect on kindling acquisition. In the present study the effect of the perforant path LFS on induction of rapid perforant path kindled seizures and synaptic transmission in the dentate gyrus was investigated. Animals were kindled by perforant path stimulation in a rapid kindling manner (12 stimulations per day). In one group of animals LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50-150 microA) was applied to perforant path, immediately after termination of each rapid kindling stimulation. Application of LFS significantly retarded the kindling acquisition and increased the number of stimulations to achieved different kindled seizure stages. LFS also prevented an increment in the slope of field excitatory postsynaptic potentials and population spike amplitude during kindling. In addition, LFS significantly reduced the marked increase in early (10-50 ms intervals) and late (300-1000 ms intervals) paired-pulse depression induced by kindling. According to obtained results, it may be suggested that LFS of perforant path has a significant antiepileptogenic effect through inhibition of synaptic transmission in dentate gyrus. Meanwhile, LFS prevents an increase in the paired-pulse depression during kindling acquisition. PMID:17576049
Synaptic mechanisms underlying cholinergic control of thalamic reticular nucleus neurons.
Beierlein, Michael
Neuronal networks of the thalamus are the target of extensive cholinergic projections from the basal forebrain and the brainstem. Activation of these afferents can regulate neuronal excitability, transmitter release, and firing patterns in thalamic networks, thereby altering the flow of sensory information during distinct behavioural states. However, cholinergic regulation in the thalamus has been primarily examined by using receptor agonist and antagonist, which has precluded a detailed understanding of the spatiotemporal dynamics that govern cholinergic signalling under physiological conditions. This review summarizes recent studies on cholinergic synaptic transmission in the thalamic reticular nucleus (TRN), a brain structure intimately involved in the control of sensory processing and the generation of rhythmic activity in the thalamocortical system. This work has shown that acetylcholine (ACh) released from individual axons can rapidly and reliably activate both pre- and postsynaptic cholinergic receptors, thereby controlling TRN neuronal activity with high spatiotemporal precision. PMID:24973413
Effects of intratympanic gentamicin on vestibular afferents and hair cells in the chinchilla.
Hirvonen, Timo P; Minor, Lloyd B; Hullar, Timothy E; Carey, John P
Gentamicin is toxic to vestibular hair cells, but its effects on vestibular afferents have not been defined. We treated anesthetized chinchillas with one injection of gentamicin (26.7 mg/ml) into the middle ear and made extracellular recordings from afferents after 5-25 (early) or 90-115 days (late). The relative proportions of regular, intermediate, and irregular afferents did not change after treatment. The spontaneous firing rate of regular afferents was lower (P < 0.001) on the treated side (early: 44.3 +/- 16.3; late: 33.9 +/- 13.2 spikes x s(-1)) than on the untreated side (54.9 +/- 16.8 spikes x s(-1)). Spontaneous rates of irregular and intermediate afferents did not change. The majority of treated afferents did not measurably respond to tilt or rotation (82% in the early group, 76% in the late group). Those that did respond had abnormally low sensitivities (P < 0.001). Treated canal units that responded to rotation had mean sensitivities only 5-7% of the values for untreated canal afferents. Treated otolith afferents had mean sensitivities 23-28% of the values for untreated otolith units. Sensitivity to externally applied galvanic currents was unaffected for all afferents. Intratympanic gentamicin treatment reduced the histological density of all hair cells by 57% (P = 0.04). The density of hair cells with calyx endings was reduced by 99% (P = 0.03), although some remaining hair cells had other features suggestive of type I morphology. Type II hair cell density was not significantly reduced. These findings suggest that a single intratympanic gentamicin injection causes partial damage and loss of vestibular hair cells, particularly type I hair cells or their calyceal afferent endings, does not damage the afferent spike initiation zones, and preserves enough hair cell synaptic activity to drive the spontaneous activity of vestibular afferents. PMID:15456806
5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders
Ciranna, Lucia; Catania, Maria Vincenza
Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD. PMID:25221471
Cooperation of NMDA and tachykinin NK 1 and NK 2 receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach
Milana Joci?; Rufina Schuligoi; Elisabeth Schöninkle; Maria A. Pabst; Peter Holzer
Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5
Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons
de Jesús Aceves, José; Rueda-Orozco, Pavel E.; Hernández, Ricardo; Plata, Víctor; Ibańez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, José
Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism. PMID:21347219
The Effects of NR2 Subunit-Dependent NMDA Receptor Kinetics on Synaptic Transmission and CaMKII Activation
Santucci, David M.; Raghavachari, Sridhar
N-Methyl-d-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function. PMID:18974824
Shared reflex pathways of group I afferents of different cat hind-limb muscles.
Harrison, P J; Jankowska, E; Johannisson, T
The convergence of group I muscle afferents of different muscle origin onto interneurones in spinal reflex pathways has been investigated using the technique of spatial facilitation of the transmission from afferents to motoneurones. The investigated pathways are those of non-reciprocal inhibition and of oligosynaptic excitation of motoneurones. Extensive convergence has been found of group I afferents from muscles operating at the same and different joints onto the interneurones interposed in both excitatory and inhibitory, disynaptic and trisynaptic pathways to motoneurones. Convergence has been found between muscle spindle Ia and/or tendon organ Ib afferents from different muscles, thereby extending observations on convergence of these subgroups of group I afferents from the same muscles. The results show that group I afferents of different muscles influence motoneurones via shared neuronal pathways and that transmission from these afferents is influenced by afferents originating in other muscles. The afferent information forwarded to individual motoneurones is therefore the ensemble picture of the length and tension of many muscles. PMID:6308242
Inhibitory effects of endomorphin-2 on excitatory synaptic transmission and the neuronal excitability of sacral parasympathetic preganglionic neurons in young rats
Chen, Ying-Biao; Huang, Fen-Sheng; Fen, Ban; Yin, Jun-Bin; Wang, Wei; Li, Yun-Qing
The function of the urinary bladder is partly controlled by parasympathetic preganglionic neurons (PPNs) of the sacral parasympathetic nucleus (SPN). Our recent work demonstrated that endomorphin-2 (EM-2)-immunoreactive (IR) terminals form synapses with ?-opioid receptor (MOR)-expressing PPNs in the rat SPN. Here, we examined the effects of EM-2 on excitatory synaptic transmission and the neuronal excitability of the PPNs in young rats (24–30 days old) using a whole-cell patch-clamp approach. PPNs were identified by retrograde labeling with the fluorescent tracer tetramethylrhodamine-dextran (TMR). EM-2 (3 ?M) markedly decreased both the amplitude and the frequency of the spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) of PPNs. EM-2 not only decreased the resting membrane potentials (RMPs) in 61.1% of the examined PPNs with half-maximal response at the concentration of 0.282 ?M, but also increased the rheobase current and reduced the repetitive action potential firing of PPNs. Analysis of the current–voltage relationship revealed that the EM-2-induced current was reversed at ?95 ± 2.5 mV and was suppressed by perfusion of the potassium channel blockers 4-aminopyridine (4-AP) or BaCl2 or by the addition of guanosine 5?-[?-thio]diphosphate trilithium salt (GDP-?-S) to the pipette solution, suggesting the involvement of the G-protein-coupled inwardly rectifying potassium (GIRK) channel. The above EM-2-invoked inhibitory effects were abolished by the MOR selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), indicating that the effects of EM-2 on PPNs were mediated by MOR via pre- and/or post-synaptic mechanisms. EM-2 activated pre- and post-synaptic MORs, inhibiting excitatory neurotransmitter release from the presynaptic terminals and decreasing the excitability of PPNs due to hyperpolarization of their membrane potentials, respectively. These inhibitory effects of EM-2 on PPNs at the spinal cord level may explain the mechanism of action of morphine treatment and morphine-induced bladder dysfunction in the clinic.
Compensatory changes in the hippocampus of somatostatin knockout mice: upregulation of somatostatin receptor 2 and its function in the control of bursting activity and synaptic transmission.
Cammalleri, Maurizio; Cervia, Davide; Dal Monte, Massimo; Martini, Davide; Langenegger, Daniel; Fehlmann, Dominique; Feuerbach, Dominik; Pavan, Barbara; Hoyer, Daniel; Bagnoli, Paola
Somatostatin-14 (SRIF) co-localizes with gamma-aminobutyric acid (GABA) in the hippocampus and regulates neuronal excitability. A role of SRIF in the control of seizures has been proposed, although its exact contribution requires some clarification. In particular, SRIF knockout (KO) mice do not exhibit spontaneous seizures, indicating that compensatory changes may occur in KO. In the KO hippocampus, we examined whether specific SRIF receptors and/or the cognate peptide cortistatin-14 (CST) compensate for the absence of SRIF. We found increased levels of both sst2 receptors (sst2) and CST, and we explored the functional consequences of sst2 compensation on bursting activity and synaptic responses in hippocampal slices. Bursting was decreased by SRIF in wild-type (WT) mice, but it was not affected by either CST or sst2 agonist and antagonist. sst4 agonist increased bursting frequency in either WT or KO. In WT, but not in KO, its effects were blocked by agonizing or antagonizing sst2, suggesting that sst2 and sst4 are functionally coupled in the WT hippocampus. Bursting was reduced in KO as compared with WT and was increased upon application of sst2 antagonist, while SRIF, CST and sst2 agonist had no effect. At the synaptic level, we observed that in WT, SRIF decreased excitatory postsynaptic potentials which were, in contrast, increased by sst2 antagonist in KO. We conclude that sst2 compensates for SRIF absence and that its upregulation is responsible for reduced bursting and decreased excitatory transmission in KO mice. We suggest that a critical density of sst2 is needed to control hippocampal activity. PMID:16706848
Facilitative interactions between vasoactive intestinal polypeptide and receptor type-selective opioids: implications for sensory afferent regulation of spinal opioid action
Nai-Jiang Liu; Alan R Gintzler
Afferent tone is known to influence spinal opioid antinociception but the underlying neurochemical events are not well defined. This study investigates the consequence on cAMP formation of the coincident activation of signal transduction sequelae initiated by an afferent transmitter and opioid using dissociated spinal cord tissue. Afferent transmission was simulated via the addition of vasoactive intestinal polypeptide (VIP), a pelvic
Peripheral innervation patterns of vestibular nerve afferents in the bullfrog utriculus
NASA Technical Reports Server (NTRS)
Baird, Richard A.; Schuff, N. R.
Vestibular nerve afferents innervating the bullfrog utriculus differ in their response dynamics and sensitivity to natural stimulation. They also supply hair cells that differ markedly in hair bundle morphology. To examine the peripheral innervation patterns of individual utricular afferents more closely, afferent fibers were labeled by the extracellular injection of horseradish peroxidase (HRP) into the vestibular nerve after sectioning the vestibular nerve medial to Scarpa's ganglion to allow the degeneration of sympathetic and efferent fibers. The peripheral arborizations of individual afferents were then correlated with the diameters of their parent axons, the regions of the macula they innervate, and the number and type of hair cells they supply. The utriculus is divided by the striola, a narrow zone of distinctive morphology, into media and lateral parts. Utiricular afferents were classified as striolar or extrastriolar according to the epithelial entrance of their parent axons and the location of their terminal fields. In general, striolar afferents had thicker parent axons, fewer subepithelial bifurcations, larger terminal fields, and more synaptic endings than afferents in extrstriolar regions. Afferents in a juxtastriolar zone, immediately adjacent to the medial striola, had innervation patterns transitional between those in the striola and more peripheral parts of the medial extrastriola. moast afferents innervated only a single macular zone. The terminal fields of striolar afferents, with the notable exception of a few afferents with thin parent axons, were generally confined to one side of the striola. Hair cells in the bullfrog utriculus have perviously been classified into four types based on hair bundle morphology. Afferents in the extrastriolar and juxtastriolar zones largely or exclusively innervated Type B hair cells, the predominant hair cell type in the utricular macula. Striolar afferents supplied a mixture of four hair cell types, but largely contacted Type B and Type C hair cells, particularly on the outer rows of the medial striola. Afferents supplying more central striolar regions innervated fewer Type B and larger numbers of Type E and Type F hair cells. Striolar afferents with thin parent axons largely supplied Type E hair cells with bulbed kniocilia in the innermost striolar rows.
High Frequency Stimulation of the Subthalamic Nucleus Leads to Presynaptic GABA(B)-Dependent Depression of Subthalamo-Nigral Afferents
Dvorzhak, Anton; Gertler, Christoph; Harnack, Daniel; Grantyn, Rosemarie
Patients with akinesia benefit from chronic high frequency stimulation (HFS) of the subthalamic nucleus (STN). Among the mechanisms contributing to the therapeutic success of HFS-STN might be a suppression of activity in the output region of the basal ganglia. Indeed, recordings in the substantia nigra pars reticulata (SNr) of fully adult mice revealed that HFS-STN consistently produced a reduction of compound glutamatergic excitatory postsynaptic currents at a time when the tetrodotoxin-sensitive components of the local field potentials had already recovered after the high frequency activation. These observations suggest that HFS-STN not only alters action potential conduction on the way towards the SNr but also modifies synaptic transmission within the SNr. A classical conditioning-test paradigm was then designed to better separate the causes from the indicators of synaptic depression. A bipolar platinum-iridium macroelectrode delivered conditioning HFS trains to a larger group of fibers in the STN, while a separate high-ohmic glass micropipette in the rostral SNr provided test stimuli at minimal intensity to single fibers. The conditioning-test interval was set to 100 ms, i.e. the time required to recover the excitability of subthalamo-nigral axons after HFS-STN. The continuity of STN axons passing from the conditioning to the test sites was examined by an action potential occlusion test. About two thirds of the subthalamo-nigral afferents were occlusion-negative, i.e. they were not among the fibers directly activated by the conditioning STN stimulation. Nonetheless, occlusion-negative afferents exhibited signs of presynaptic depression that could be eliminated by blocking GABA(B) receptors with CGP55845 (1 µM). Further analysis of single fiber-activated responses supported the proposal that the heterosynaptic depression of synaptic glutamate release during and after HFS-STN is mainly caused by the tonic release of GABA from co-activated striato-nigral afferents to the SNr. This mechanism would be consistent with a gain-of-function hypothesis of DBS. PMID:24376521
Hair cell synaptic ribbons are essential for synchronous auditory signalling.
Khimich, Darina; Nouvian, Régis; Pujol, Rémy; Tom Dieck, Susanne; Egner, Alexander; Gundelfinger, Eckart D; Moser, Tobias
Hearing relies on faithful synaptic transmission at the ribbon synapse of cochlear inner hair cells (IHCs). At present, the function of presynaptic ribbons at these synapses is still largely unknown. Here we show that anchoring of IHC ribbons is impaired in mouse mutants for the presynaptic scaffolding protein Bassoon. The lack of active-zone-anchored synaptic ribbons reduced the presynaptic readily releasable vesicle pool, and impaired synchronous auditory signalling as revealed by recordings of exocytic IHC capacitance changes and sound-evoked activation of spiral ganglion neurons. Both exocytosis of the hair cell releasable vesicle pool and the number of synchronously activated spiral ganglion neurons co-varied with the number of anchored ribbons during development. Interestingly, ribbon-deficient IHCs were still capable of sustained exocytosis with normal Ca2+-dependence. Endocytic membrane retrieval was intact, but an accumulation of tubular and cisternal membrane profiles was observed in ribbon-deficient IHCs. We conclude that ribbon-dependent synchronous release of multiple vesicles at the hair cell afferent synapse is essential for normal hearing. PMID:15829963
Sleep deprivation-induced alterations in excitatory synaptic transmission in the CA1 region of the rat hippocampus
McDermott, Carmel M; Hardy, Mattie N; Bazan, Nicolas G; Magee, Jeffrey C
Although the function of sleep remains elusive, there is compelling evidence to suggest that sleep plays an important role in learning and memory. A number of studies have now shown that sleep deprivation (SD) results in significant impairment of long-term potentiation (LTP) in the hippocampus. In this study, we have attempted to determine the mechanisms responsible for this impairment. After 72 h SD using the multiple-platform technique, we observed a reduction in the whole-cell recorded NMDA/AMPA ratio of CA1 pyramidal cells in response to Schaffer collateral stimulation. This impairment was specific to sleep deprivation as rats placed over a single large platform, which allowed sleep, had a normal NMDA/AMPA ratio. mEPSCs evoked by local application of a high osmolarity solution revealed no differences in the AMPA receptor function. NMDA currents recorded from outside-out patches excised from the distal dendrites of CA1 cells displayed a reduction in amplitude after SD. While there were no alterations in the glutamate sensitivity, channel open probability or the single channel conductance of the receptor, a crosslinking assay demonstrated that the NR1 and NR2A subunits of NMDA receptors were preferentially retained in the cytoplasm after SD, indicating that SD alters NMDAR surface expression. In summary, we have identified a potential mechanism underlying SD-induced LTP impairment. This synaptic alteration may underlie the cognitive deficits seen following sleep deprivation and could represent a target for future intervention studies. PMID:16322058
Roles of neuronal NK1 and NK3 receptors in synaptic transmission during motility reflexes in the guinea-pig ileum
Johnson, P J; Bornstein, J C; Burcher, E
The role of NK1 and NK3 receptors in synaptic transmission between myenteric neurons during motility reflexes in the guinea-pig ileum was investigated by recording intracellularly the reflex responses of the circular muscle to distension or compression of the mucosal villi. Experiments were performed in a three-chambered organ bath that enabled drugs to be selectively applied to different sites along the reflex pathways.When applied in the recording chamber, an NK1 receptor antagonist, SR140333 (100?nM), reduced by 40–50% the amplitudes of inhibitory junction potentials (i.j.ps) evoked in the circular muscle by activation of descending reflex pathways. This effect was abolished when synaptic transmission in the stimulus region was blocked with physiological saline containing 0.1?mM Ca2+ plus 10?mM Mg2+, leaving only the component of the descending reflex pathway conducted via long anally directed collaterals of intrinsic sensory neurons.SR140333 (100?nM) had no effect on descending reflex i.j.ps when applied to the stimulus region. Ascending reflexes were also unaffected by SR140333 in the stimulus region or between the stimulus and recording sites.Septide (10?nM), an NK1 receptor agonist, enhanced descending reflexes by 30–60% when in the recording chamber. [Sar9,Met(O2)11]substance P had no effect at 10?nM, but potentiated distension-evoked reflexes at 100?nM.A selective NK3 receptor antagonist, SR142801 (100?nM), when applied to the stimulus region, reduced the amplitude of descending reflex responses to compression by 40%, but had no effect on responses to distension. SR142801 (100?nM) had no effect when applied to other regions of the descending reflex pathways.SR142801 (100?nM) only inhibited ascending reflexes when applied at the recording site. However, after nicotinic transmission in the stimulus region was blocked, SR142801 (100?nM) at this site reduced responses to compression.Contractions of the circular muscle of isolated rings of ileum evoked by low concentrations of septide, but not [Sar9,Met(O2)11]substance P, were potentiated by tetrodotoxin (300?nM).Contractile responses evoked by an NK3 receptor agonist, senktide, were non-competitively inhibited by SR142801. After excitatory neuromuscular transmission was blocked, senktide produced inhibitory responses that were also antagonised by SR142801, but to a lesser extent and in an apparently competitive manner.These results indicate that tachykinins acting via NK1 receptors partly mediate transmission to inhibitory motor neurons. NK3 receptors play a role in transmission from intrinsic sensory neurons and from ascending interneurons to excitatory motor neurons during motility reflexes. PMID:9723948
Implications of All-or-None Synaptic Transmission and Short-Term Depression beyond Vesicle Depletion: A Computational Study
Victor Matveev; Xiao-Jing Wang
The all-or-none character of transmission at central synapses is commonly viewed as evidence that only one vesicle can be released per action potential at a single release site. This inter- pretation is still a matter of debate; its resolution is important for our understanding of the nature of quantal response. In this work we explore observable consequences of the univesicular
Cellular/Molecular StabilizationofAxonBranchDynamicsbySynapticMaturation
form and mature. To examine the role of synaptogenesis and synaptic maturation in the structural of synaptogenesis: increases in presynaptic punctum intensity are detectable within minutes of punctum emergence; Xenopus; synaptogenesis Introduction Patterned neural activity and synaptic transmission guide
Differential modulation of synaptic transmission by calcium chelators in young and aged hippocampal CA1 neurons: evidence for altered calcium homeostasis in aging.
Ouanounou, A; Zhang, L; Charlton, M P; Carlen, P L
The effects of membrane-permeant Ca2+ chelators on field EPSPs (fEPSPs) were measured in the hippocampal CA1 region of brain slices from young (2-4 months) and old (24-27 months) Fischer 344 rats. BAPTA-AM depressed fEPSPs in young slices by up to 70% but enhanced fEPSPs by 30% in aged slices. EGTA-AM, with slower binding kinetics, did not affect fEPSPs from young slices but enhanced fEPSPs in aged slices. BAPTA derivatives with calcium dissociation constants (Kd) of 0.2-3.5 microM reduced or enhanced fEPSPs in young and aged slices, respectively, but 5',5'-dinitro BAPTA-AM (Kd of approximately 7000 microM) had no effect. Frequency facilitation of the fEPSPs occurred in young, but not in aged, slices, except when BAPTA-AM or EGTA-AM was perfused onto aged slices. The differential effects of BAPTA-AM in young and old slices were eliminated by perfusing with a low Ca2+-high Mg2+ saline or with the calcium blocker Co2+. These data suggest that intracellular Ca2+ regulation is altered and raised in aged neurons. Cell-permeant calcium buffers may be able to "ameliorate" deficits in synaptic transmission in the aged brain. PMID:9920654
Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy.
Kwong, Anna Ka-Yee; Ho, Alvin Chi-Chung; Fung, Cheuk-Wing; Wong, Virginia Chun-Nei
Epileptic Encephalopathy (EE) is a heterogeneous condition in which cognitive, sensory and/or motor functions deteriorate as a consequence of epileptic activity, which consists of frequent seizures and/or major interictal paroxysmal activity. There are various causes of EE and they may occur at any age in early childhood. Genetic mutations have been identified to contribute to an increasing number of children with early onset EE which had been previously considered as cryptogenic. We identified 26 patients with Infantile Epileptic Encephalopathy (IEE) of unknown etiology despite extensive workup and without any specific epilepsy syndromic phenotypes. We performed genetic analysis on a panel of 7 genes (ARX, CDKL5, KCNQ2, PCDH19, SCN1A, SCN2A, STXBP1) and identified 10 point mutations [ARX (1), CDKL5 (3), KCNQ2 (2), PCDH19 (1), SCN1A (1), STXBP1 (2)] as well as one microdeletion involving both SCN1A and SCN2A. The high rate (42%) of mutations suggested that genetic testing of this IEE panel of genes is recommended for cryptogenic IEE with no etiology identified. These 7 genes are associated with channelopathies or synaptic transmission and we recommend early genetic testing if possible to guide the treatment strategy. PMID:25951140
?-Opioid Receptor-Mediated Inhibition of Intercalated Neurons and Effect on Synaptic Transmission to the Central Amygdala
Blaesse, Peter; Goedecke, Lena; Bazelot, Michaël; Capogna, Marco; Pape, Hans-Christian
The amygdala is a key region for the processing of information underlying fear, anxiety, and fear extinction. Within the local neuronal networks of the amygdala, a population of inhibitory, intercalated neurons (ITCs) modulates the flow of information among various nuclei of amygdala, including the basal nucleus (BA) and the centromedial nucleus (CeM) of the amygdala. These ITCs have been shown to be important during fear extinction and are target of a variety of neurotransmitters and neuropeptides. Here we provide evidence that the activation of ?-opioid receptors (MORs) by the specific agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin) hyperpolarizes medially located ITCs (mITCs) in acute brain slices of mice. Moreover, we use whole-cell patch-clamp recordings in combination with local electrical stimulation or glutamate uncaging to analyze the effect of MOR activation on local microcircuits. We show that the GABAergic transmission between mITCs and CeM neurons is attenuated by DAMGO, whereas the glutamatergic transmission on CeM neurons and mITCs is unaffected. Furthermore, MOR activation induced by theta burst stimulation in BA suppresses plastic changes of feedforward inhibitory transmission onto CeM neurons as revealed by the MOR antagonist CTAP d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2. In summary, the mITCs constitute a target for the opioid system, and therefore, the activation of MOR in ITCs might play a central role in the modulation of the information processing between the basolateral complex of the amygdala and central nuclei of the amygdala. PMID:25972162
Neurons in laminae III and IV of the rat spinal cord with the neurokinin-1 receptor receive few contacts from unmyelinated primary afferents which do not contain substance P
H Sakamoto; R. C Spike; A. J Todd
We have previously demonstrated that neurons in laminae III and IV of the spinal dorsal horn which possess the neurokinin-1 receptor and have long dorsal dendrites receive a major synaptic input from substance P-containing primary afferents and a more limited input from myelinated afferents. In the present study we have carried out a quantitative analysis of the contacts which cells
Efferent Control of Hair Cell and Afferent Responses in the Semicircular Canals
Boyle, Richard; Rabbitt, Richard D.; Highstein, Stephen M.
The sensations of sound and motion generated by the inner ear are controlled by the brain through extensive centripetal innervation originating within the brain stem. In the semicircular canals, brain stem efferent neurons make synaptic contacts with mechanosensory hair cells and with the dendrites of afferent neurons. Here, we examine the relative contributions of efferent action on hair cells and afferents. Experiments were performed in vivo in the oyster toadfish, Opsanus tau. The efferent system was activated via electrical pulses to the brain stem and sensory responses to motion stimuli were quantified by simultaneous voltage recording from afferents and intracellular current- and/or voltage-clamp recordings from hair cells. Results showed synaptic inputs to both afferents and hair cells leading to relatively long-latency intracellular signaling responses: excitatory in afferents and inhibitory in hair cells. Generally, the net effect of efferent action was an increase in afferent background discharge and a simultaneous decrease in gain to angular motion stimuli. Inhibition of hair cells was likely the result of a ligand-gated opening of a major basolateral conductance. The reversal potential of the efferent-evoked current was just below the hair cell resting potential, thus resulting in a small hyperpolarization. The onset latency averaged about 90 ms and latency to peak response was 150–400 ms. Hair cell inhibition often outlasted afferent excitation and, in some cases, latched hair cells in the "off" condition for >1 s following cessation of stimulus. These features endow the animal with a powerful means to adjust the sensitivity and dynamic range of motion sensation. PMID:19571186
Lipid signaling: Sleep, synaptic plasticity, and neuroprotection
Chu Chen; Nicolas G. Bazan
Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K,
Variation in response dynamics of regular and irregular vestibular-nerve afferents during sinusoidal head rotations and currents in the chinchilla.
Kim, Kyu-Sung; Minor, Lloyd B; Della Santina, Charles C; Lasker, David M
In mammals, vestibular-nerve afferents that innervate only type I hair cells (calyx-only afferents) respond nearly in phase with head acceleration for high-frequency motion, whereas afferents that innervate both type I and type II (dimorphic) or only type II (bouton-only) hair cells respond more in phase with head velocity. Afferents that exhibit irregular background discharge rates have a larger phase lead re-head velocity than those that fire more regularly. The goal of this study was to investigate the cause of the variation in phase lead between regular and irregular afferents at high-frequency head rotations. Under the assumption that externally applied galvanic currents act directly on the nerve, we derived a transfer function describing the dynamics of a semicircular canal and its hair cells through comparison of responses to sinusoidally modulated head velocity and currents. Responses of all afferents were fit well with a transfer function with one zero (lead term). Best-fit lead terms describing responses to current for each group of afferents were similar to the lead term describing responses to head velocity for regular afferents (0.006 s + 1). This finding indicated that the pre-synaptic and synaptic inputs to regular afferents were likely to be pure velocity transducers. However, the variation in phase lead between regular and irregular afferents could not be explained solely by the ratio of type I to II hair cells (Baird et al 1988), suggesting that the variation was caused by a combination of pre- (type of hair cell) and post-synaptic properties. PMID:21369854
Modulatory effects of the novel TrkB receptor agonist 7,8-dihydroxyflavone on synaptic transmission and intrinsic neuronal excitability in mouse visual cortex in vitro.
Marongiu, Daniele; Imbrosci, Barbara; Mittmann, Thomas
7,8-Dihydroxyflavone (7,8 DHF) is a new recently identified TrkB receptor agonist, which possesses a potent neurotrophic activity and shares many physiological properties with the neurotrophin "Brain Derived Neurotrophic Factor" (BDNF). However, its precise mechanism of action at the cellular level has not been clarified yet. In the present study we explored the effects of this agent on synaptic and intrinsic neuronal properties by performing whole-cell patch clamp recordings from layer 2/3 pyramidal neurons. Incubation of acute cortical slices with 7,8-DHF (20 µM) for 30 min caused a selective reduction in the strength of GABAergic inhibition. The amplitude of evoked inhibitory postsynaptic currents (eIPSCs) was significantly reduced to 48.2±8.9% of the control level. This might be a result of decreased presynaptic ?-aminobutyric acid (GABA) release, as suggested by the reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) (control: 10.7±0.7 Hz, 7,8 DHF: 7.9±0.6 Hz) and increased Paired-Pulse Ratio (PPR) (50±8.9%). Conversely, the glutamatergic transmission was unaffected. Moreover, 7,8-DHF was able to alter the intrinsic neuronal excitability, by significantly increasing spike frequency and input resistance (control: 243.75±23.4 M?, 7,8 DHF: 338.5±25.1 M?). Remarkably, all reported effects were abolished in presence of the TrkB receptor antagonist K252a indicating a direct involvement of TrkB receptors in the action of 7,8-DHF. These data indicate that 7,8-DHF might be one promising candidate for the development of a new class of drugs called "BDNF mimetics" for the future treatment of cognitive disorders and neurodegenerative diseases. PMID:23567067
Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals.
Martorana, Alessandro; Di Lorenzo, Francesco; Manenti, Guglielmo; Semprini, Roberta; Koch, Giacomo
Current treatment options for patients with Alzheimer's disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (A?) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of A? early in the cascade of amyloidogenic events, and by its ?-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity. PMID:25295005
Homotaurine Induces Measurable Changes of Short Latency Afferent Inhibition in a Group of Mild Cognitive Impairment Individuals
Martorana, Alessandro; Di Lorenzo, Francesco; Manenti, Guglielmo; Semprini, Roberta; Koch, Giacomo
Current treatment options for patients with Alzheimer's disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (A?) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of A? early in the cascade of amyloidogenic events, and by its ?-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity. PMID:25295005
Growth factors in synaptic function
Poon, Vivian Y.; Choi, Sojoong; Park, Mikyoung
Synapses are increasingly recognized as key structures that malfunction in disorders like schizophrenia, mental retardation, and neurodegenerative diseases. The importance and complexity of the synapse has fuelled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. In this regard, neurotrophic factors such as netrin, Wnt, transforming growth factor-? (TGF-?), tumor necrosis factor-? (TNF-?), and others have gained prominence for their ability to regulate synaptic function. Several of these factors were first implicated in neuroprotection, neuronal growth, and axon guidance. However, their roles in synaptic development and function have become increasingly clear, and the downstream signaling pathways employed by these factors have begun to be elucidated. In this review, we will address the role of these factors and their downstream effectors in synaptic function in vivo and in cultured neurons. PMID:24065916
NSDL National Science Digital Library
Melissa Yoshioka
In this outdoor activity, learners review the parts of the synapse and their functions by playing a game. The object of the game is to get as many neurotransmitters across the synapse to the dendrite without being caught (deactivated) by the enzyme. This game models the process by which enzymes break down neurotransmitters (e.g., acetylcholine) in the synaptic cleft.
BL4234 Synaptic transmission Organiser: Dr W.-C. Li (Prof. K.T. Sillar, Dr G.B. Miles, Dr. W.J. Heitler)
Brierley, Andrew
will include topics such as: Synaptic vesicle release machinery, co-release of multiple neurotransmitters neurotransmitters are released at chemical synapses. · How transmitters act on their postsynaptic target to generate
Intrinsic primary afferent neuronsof the intestine
After a long period of inconclusive observations, the intrinsic primary afferent neurons of the intestine have been identified. The intestine is thus equipped with two groups of afferent neurons, those with cell bodies in cranial and dorsal root ganglia, and these recently identified afferent neurons with cell bodies in the wall of the intestine.The first, tentative, identification of intrinsic primary
Spike-Based Synaptic Plasticity and the Emergence of Direction Selective Simple Cells: Simulation Results
Nissim J. Buchs; Walter Senn
Direction selectivity (DS) of simple cells in the primary visual cortex was recently suggested to arise from short-term synaptic depression in thalamocortical afferents (Chance F, Nelson S, Abbott L (1998), J. Neuroscience 18(12): 4785-4799). In the model, two groups of afferents with spatially displaced receptive fields project through either depressing and non-depressing synapses onto the V1 cell. The degree of
Spike-Based Synaptic Plasticity and the Emergence of Direction Selective Simple Cells: Simulation Results
N. J. Buchs; W. Senn
Direction selectivity (DS) of simple cells in the primary visual cortex was recently suggested to arise from short-term synaptic depression in thalamocortical afferents (Chance F, Nelson S, Abbott L (1998), J. Neuroscience 18(12): 4785–4799). In the model, two groups of afferents with spatially displaced receptive fields project through either depressing and non-depressing synapses onto the V1 cell. The degree of
Perceptual responses to microstimulation of single afferents innervating joints, muscles and skin of the human hand.
Macefield, G; Gandevia, S C; Burke, D
1. Microneurographic techniques were used to isolate single afferent axons within cutaneous and motor fascicles of the median and ulnar nerves at the wrist in thirteen subjects. Of the sixty-five identified afferents, eleven innervated the interphalangeal and metacarpophalangeal joints, sixteen innervated muscle spindles, three innervated Golgi tendon organs and thirty-five supplied the glabrous skin of the hand. 2. Intrafascicular stimulation through the recording microelectrode, using trains of constant-voltage positive pulses (0.3-0.8 V, 0.1-0.2 ms, 1-100 Hz) or constant-current biphasic pulses (0.4-13.0 microA, 0.2 ms, 1-100 Hz), evoked specific sensations from sites associated with some afferent species but not others. 3. Microstimulation of eight of the eleven joint afferent sites (73%) evoked specific sensations. With four, subjects reported innocuous deep sensations referred to the relevant joint. With the other four, the subjects reported a sensation of joint displacement that partially reflected the responsiveness of the afferents to joint rotation. 4. Microstimulation of fourteen of the sixteen muscle spindle afferent sites (88%) generated no perceptions when the stimuli did not produce overt movement. However, subjects could correctly detect the slight movements generated when the stimuli excited the motor axons to the parent muscle. 5. With seven of the nine rapidly adapting (type RA or FAI) cutaneous afferents (88%) microstimulation evoked sensations of 'flutter-vibration', and with two of eight slowly adapting (type SAI) afferents (25%) it evoked sensations of 'sustained pressure'. Of the eighteen SAII afferents, which were classified as such by their responses to planar skin stretch, the majority (83%) generated no perceptions, confirming previous work, but three evoked sensations of movements or pressure. 6. The present results suggest a relatively secure transmission of joint afferent traffic to perceptual levels, and it is concluded that the human brain may be able to synthesize meaningful information on joint displacement on the basis of impulses in a single joint afferent. This could partly compensate for the low responsiveness of individual joint afferents within the physiological range of joint displacements. Although single muscle spindle afferents can adequately encode joint position and movement, the results suggest that the brain needs the information from more than one muscle spindle afferent to perceive changes in joint angle. PMID:2148951
Jaw-muscle spindle afferent feedback to the cervical spinal cord in the rat
Dean Dessem; Pifu Luo
Putative synaptic contacts between masticatory-muscle spindle afferents and brainstem neurons which project to the cervical\\u000a spinal cord were studied in rats by combining retrograde and intracellular neuronal labeling. Spinal cord projecting neurons\\u000a were retrogradely labeled via injection of horseradish peroxidase unilaterally or bilaterally into cervical spinal cord segments\\u000a C2 through C5. Twenty-four hours after the injection of horseradish peroxidase, one
Pharmacology of airway afferent nerve activity
Undem, Bradley J; Carr, Michael J
Afferent nerves in the airways serve to regulate breathing pattern, cough, and airway autonomic neural tone. Pharmacologic agents that influence afferent nerve activity can be subclassified into compounds that modulate activity by indirect means (e.g. bronchial smooth muscle spasmogens) and those that act directly on the nerves. Directly acting agents affect afferent nerve activity by interacting with various ion channels and receptors within the membrane of the afferent terminals. Whether by direct or indirect means, most compounds that enter the airspace will modify afferent nerve activity, and through this action alter airway physiology. PMID:11686889
Interneurones in pathways from group II muscle afferents in sacral segments of the feline spinal cord.
Jankowska, E; Riddell, J S
1. Properties of dorsal horn interneurones that process information from group II muscle afferents in the sacral segments of the spinal cord have been investigated in the cat using both intracellular and extracellular recording. 2. The interneurones were excited by group II muscle afferents and cutaneous afferents but not by group I muscle afferents. They were most effectively excited by group II afferents of the posterior biceps, semitendinosus, triceps surae and quadriceps muscle nerves and by cutaneous afferents running in the cutaneous femoris, pudendal and sural nerves. The earliest synaptic actions were evoked monosynaptically and were very tightly locked to the stimuli. 3. EPSPs evoked monosynaptically by group II muscle afferents and cutaneous afferents of the most effective nerves were often cut short by disynaptic IPSPs. As a consequence of this negative feedback the EPSPs gave rise to single or double spike potentials and only a minority of interneurones responded with repetitive discharges. However, the neurones that did respond repetitively did so at a very high frequency of discharges (0.8-1.2 ms intervals between the first 2-3 spikes). 4. Sacral dorsal horn group II interneurones do not appear to act directly upon motoneurones because: (i) these interneurones are located outside the area within which last order interneurones have previously been found and (ii) the latencies of PSPs evoked in motoneurones by stimulation of the posterior biceps and semitendinosus, cutaneous femoris and pudendal nerves (i.e. the main nerves providing input to sacral interneurones) are compatible with a tri- but not with a disynaptic coupling. Spatial facilitation of EPSPs and IPSPs following synchronous stimulation of group II and cutaneous afferents of these nerves shows, however, that sacral interneurones may induce excitation or inhibition of motoneurones via other interneurones. 5. Comparison of the properties of group II interneurones in the sacral segments with those of previously studied group II interneurones in the midlumbar segments leads to the conclusion that these two populations of neurones are specialized for the processing of information from different muscles and skin areas. In addition, equivalents of only one of the two subpopulations of midlumbar interneurones have been found at the level of the pudendal nucleus: neurones with input from group II but not from group I muscle afferents. Neurones integrating information from group I and II muscle afferents and in direct contact with motoneurones thus seem to be scarce in the sacral segments.(ABSTRACT TRUNCATED AT 400 WORDS) Images Figure 2 Figure 5 PMID:8006828
Afferent Deprivation Elicits a Transcriptional Response Associated with Neuronal Survival After a Critical Period in the Mouse Cochlear Nucleus
Harris, Julie A.; Iguchi, Fukuichiro; Seidl, Armin H.; Lurie, Diana I.; Rubel, Edwin W
The mechanisms underlying enhanced plasticity of synaptic connections and susceptibilities to manipulations of afferent activity in developing sensory systems are not well understood. One example is the rapid and dramatic neuron death that occurs after removal of afferent input to the cochlear nucleus (CN) of young mammals and birds. The molecular basis of this critical period of neuronal vulnerability and the transition to survival independent of afferent input remains to be defined. Here we used microarray analyses, real time RT PCR, and immunohistochemistry of the mouse CN to show that deafferentation results in strikingly different sets of regulated genes in vulnerable (postnatal day (P) 7) and invulnerable (P21) CN. An unexpectedly large set of immune-related genes was induced by afferent deprivation after the critical period, which corresponded with glial proliferation over the same time frame. Apoptotic gene expression was not highly regulated in the vulnerable CN after afferent deprivation but, surprisingly, did increase after deafferentation at P21, when all neurons ultimately survive. Pharmacological activity blockade in the 8th nerve mimicked afferent deprivation for only a subset of the afferent deprivation regulated genes, indicating the presence of an additional factor not dependent on action potential-mediated signaling that is also responsible for transcriptional changes. Overall, our results suggest that the cell death machinery during this critical period is mainly constitutive, whereas after the critical period neuronal survival could be actively promoted by both constitutive and induced gene expression. PMID:18945907
Monosynaptic connections between primary afferents and giant neurons in the turtle spinal dorsal horn.
Fernández, A; Radmilovich, M; Russo, R E; Hounsgaard, J; Trujillo-Cenóz, O
This paper reports the occurrence of monosynaptic connections between dorsal root afferents and a distinct cell type-the giant neuron-deep in the dorsal horn of the turtle spinal cord. Light microscope studies combining Nissl stain and transganglionic HRP-labeling of the primary afferents have revealed the occurrence of axosomatic and axodendritic contacts between labeled boutons and giant neurons. The synaptic nature of these contacts has been confirmed by use of electron microscope procedures involving the partial three-dimensional reconstruction of identified giant neurons. Intracellular recording in spinal cord slices provided functional evidence indicating the monosynaptic connections between dorsal root afferents and giant neurons. The recorded neurons were morphologically identified by means of biocytin injection and with avidin conjugates. Electrical stimulation of the ipsilateral dorsal roots evoked synaptic responses with short, fixed latencies (1.6-5.6 ms), which remained unchanged at high frequencies (10 Hz). Excitatory polysynaptic potentials were also observed. By means of pharmacological procedures the short-latency response was dissected in two components: one insensitive to tetrodotoxin, the other abolished by the drug. The toxin-resistant component was presumed to be sustained by small-diameter C fibers. The synaptic response was mainly mediated by the glutamate-AMPA receptor subtype; however, a small component mediated by NMDA receptor was also present. PMID:8801115
Transmitter timecourse in the synaptic cleft: its role in central synaptic function
J. D Clements
The speed of clearance of transmitter from the cleft influences many aspects of synaptic function, including the timecourse of the postsynaptic response and the peak postsynaptic receptor occupancy. The timecourse of transmitter clearance can be estimated either by detailed theoretical modelling, or from the attenuation of synaptic transmission produced by a low-affinity competitive antagonist. These approaches have been applied to
Novel Afferent Terminal Structure in the Crista Ampullaris of the Goldfish, Carassius auratus
NASA Technical Reports Server (NTRS)
Lanford, Pamela J.; Popper, Arthur N.
Using transmission electron microscopy, we have identified a new type of afferent terminal structure in the crista ampullaris of the goldfish Carassius auratus. In addition to the bouton-type afferent terminals previously described in the ear of this species, the crista also contained enlarged afferent terminals that enveloped a portion of the basolateral hair cell membrane. The hair cell membrane was evaginated and protruded into the afferent terminal in a glove-and-finger configuration. The membranes of the two cells were regularly aligned in the protruded region of the contact and had a distinct symmetrical electron density. The electron-dense profiles of these contacts were easily identified and were present in every crista sampled. In some cases, efferent terminals synapsed onto the afferents at a point where the hair cell protruded into the terminal. The ultrastructural similarities of the goldfish crista afferents to calyx afferents found in amniotes (birds, reptiles, and mammals) are discussed. The results of the study support the hypothesis that structural variation in the vertebrate inner ear may have evolved much earlier in evolution than previously supposed.
Connections between thoraco-coxal proprioceptive afferents and motor neurons in the locust.
Wildman, M
The position of the coxal segment of the locust hind leg relative to the thorax is monitored by a variety of proprioceptors, including three chordotonal organs and a myochordotonal organ. The sensory neurons of two of these proprioceptors, the posterior joint chordotonal organ (pjCO) and the myochordotonal organ (MCO), have axons in the purely sensory metathoracic nerve 2C (N2C). The connections made by these afferents with metathoracic motor neurons innervating thoraco-coxal and wing muscles were investigated by electrical stimulation of N2C and by matching postsynaptic potentials in motor neurons with afferent spikes in N2C. Stretch applied to the anterior rotator muscle of the coxa (M121), with which the MCO is associated, evoked sensory spikes in N2C. Some of the MCO afferent neurons make direct excitatory chemical synaptic connections with motor neurons innervating the thoraco-coxal muscles M121, M126 and M125. Parallel polysynaptic pathways via unidentified interneurons also exist between MCO afferents and these motor neurons. Connections with the common inhibitor 1 neuron and motor neurons innervating the thoraco-coxal muscles M123/4 and wing muscles M113 and M127 are polysynaptic. Afferents of the pjCO also make polysynaptic connections with motor neurons innervating thoraco-coxal and wing muscles, but no evidence for monosynaptic pathways was found. PMID:10637173
Postsynaptic hyperpolarization increases the strength of AMPA-mediated synaptic transmission at large synapses between mossy fibers and CA3 pyramidal cells
Nicola Berretta; Aleksej V Rossokhin; Alexander M Kasyanov; Maxim V Sokolov; Enrico Cherubini; Leon L Voronin
In chemical synapses information flow is polarized. However, the postsynaptic cells can affect transmitter release via retrograde chemical signaling. Here we explored the hypothesis that, in large synapses, having large synaptic cleft resistance, transmitter release can be enhanced by electrical (ephaptic) signaling due to depolarization of the presynaptic release site induced by the excitatory postsynaptic current itself. The hypothesis predicts
Central Vagal Afferent Endings Mediate Reduction of Food Intake by Melanocortin-3/4 Receptor Agonist
Shiina, Hiroko; Ritter, Robert C.
Injection of the melanocortin-3/4 receptor agonist melanotan-II (MTII) into the nucleus of the solitary tract (NTS) produces rapid and sustained reduction of food intake. Melanocortin-4 receptors (MC4Rs) are expressed by vagal afferent endings in the NTS, but it is not known whether these endings participate in MTII-induced reduction of food intake. In experiments described here, we evaluated the contribution of central vagal afferent endings in MTII-induced reduction of food intake. Examination of rat hindbrain sections revealed that neuronal processes expressing immunoreactivity for the endogenous MC4R agonist ?-melanoctyte-stimulating hormone course parallel and wrap around anterogradely labeled vagal afferent endings in the NTS and thus are aptly positioned to activate vagal afferent MC4Rs. Furthermore, MTII and endogenous MC4R agonists increased protein kinase A (PKA)-catalyzed phosphorylation of synapsin I in vagal afferent endings, an effect known to increase synaptic strength by enhancing neurotransmitter release in other neural systems. Hindbrain injection of a PKA inhibitor, KT5720, significantly attenuated MTII-induced reduction of food intake and the increase in synapsin I phosphorylation. Finally, unilateral nodose ganglion removal, resulting in degeneration of vagal afferent endings in the ipsilateral NTS, abolished MTII-induced synapsin I phosphorylation ipsilateral to nodose ganglion removal. Moreover, reduction of food intake following MTII injection into the NTS ipsilateral to nodose ganglion removal was significantly attenuated, whereas the response to MTII was not diminished when injected into the contralateral NTS. Altogether, our results suggest that reduction of food intake following hindbrain MC4R activation is mediated by central vagal afferent endings. PMID:25232103
Utricular afferents: morphology of peripheral terminals.
Huwe, J A; Logan, G J; Williams, B; Rowe, M H; Peterson, E H
The utricle provides critical information about spatiotemporal properties of head movement. It comprises multiple subdivisions whose functional roles are poorly understood. We previously identified four subdivisions in turtle utricle, based on hair bundle structure and mechanics, otoconial membrane structure and hair bundle coupling, and immunoreactivity to calcium-binding proteins. Here we ask whether these macular subdivisions are innervated by distinctive populations of afferents to help us understand the role each subdivision plays in signaling head movements. We quantified the morphology of 173 afferents and identified six afferent classes, which differ in structure and macular locus. Calyceal and dimorphic afferents innervate one striolar band. Bouton afferents innervate a second striolar band; they have elongated terminals and the thickest processes and axons of all bouton units. Bouton afferents in lateral (LES) and medial (MES) extrastriolae have small-diameter axons but differ in collecting area, bouton number, and hair cell contacts (LES > MES). A fourth, distinctive population of bouton afferents supplies the juxtastriola. These results, combined with our earlier findings on utricular hair cells and the otoconial membrane, suggest the hypotheses that MES and calyceal afferents encode head movement direction with high spatial resolution and that MES afferents are well suited to signal three-dimensional head orientation and striolar afferents to signal head movement onset. PMID:25632074
Reciprocal Synapses Between Outer Hair Cells and their Afferent Terminals: Evidence for a Local Neural Network in the Mammalian Cochlea
Thiers, Fabio A.; Nadol , Joseph B.
Cochlear outer hair cells (OHCs) serve both as sensory receptors and biological motors. Their sensory function is poorly understood because their afferent innervation, the type-II spiral ganglion cell, has small unmyelinated axons and constitutes only 5% of the cochlear nerve. Reciprocal synapses between OHCs and their type-II terminals, consisting of paired afferent and efferent specialization, have been described in the primate cochlea. Here, we use serial and semi-serial-section transmission electron microscopy to quantify the nature and number of synaptic interactions in the OHC area of adult cats. Reciprocal synapses were found in all OHC rows and all cochlear frequency regions. They were more common among third-row OHCs and in the apical half of the cochlea, where 86% of synapses were reciprocal. The relative frequency of reciprocal synapses was unchanged following surgical transection of the olivocochlear bundle in one cat, confirming that reciprocal synapses were not formed by efferent fibers. In the normal ear, axo-dendritic synapses between olivocochlear terminals and type-II terminals and/or dendrites were as common as synapses between olivocochlear terminals and OHCs, especially in the first row, where, on average, almost 30 such synapses were seen in the region under a single OHC. The results suggest that a complex local neuronal circuitry in the OHC area, formed by the dendrites of type-II neurons and modulated by the olivocochlear system, may be a fundamental property of the mammalian cochlea, rather than a curiosity of the primate ear. This network may mediate local feedback control of, and bidirectional communication among, OHCs throughout the cochlear spiral. PMID:18688678
Channeling satiation: a primer on the role of TRP channels in the control of glutamate release from vagal afferent neurons.
Wu, Shaw-wen; Fenwick, Axel J; Peters, James H
Obesity results from the chronic imbalance between food intake and energy expenditure. To maintain homeostasis, the brainstem nucleus of the solitary tract (NTS) integrates peripheral information from visceral organs and initiates reflex pathways that control food intake and other autonomic functions. This peripheral-to-central neural communication occurs through activation of vagal afferent neurons which converge to form the solitary tract (ST) and synapse with strong glutamatergic contacts onto NTS neurons. Vagal afferents release glutamate containing vesicles via three distinct pathways (synchronous, asynchronous, and spontaneous) providing multiple levels of control through fast synaptic neurotransmission at ST-NTS synapses. While temperature at the NTS is relatively constant, vagal afferent neurons express an array of thermosensitive ion channels named transient receptor potential (TRP) channels. Here we review the evidence that TRP channels pre-synaptically control quantal glutamate release and examine the potential roles of TRP channels in vagally mediated satiety signaling. We summarize the current literature that TRP channels contribute to asynchronous and spontaneous release of glutamate which can distinctly influence the transfer of information across the ST-NTS synapse. In other words, multiple glutamate vesicle release pathways, guided by afferent TRP channels, provide for robust while adaptive neurotransmission and expand our understanding of vagal afferent signaling. PMID:25290762
Converging axons collectively initiate and maintain synaptic selectivity in a constantly remodeling sensory organ.
Pujol-Martí, Jesús; Faucherre, Adčle; Aziz-Bose, Razina; Asgharsharghi, Amir; Colombelli, Julien; Trapani, Josef G; López-Schier, Hernán
Sensory receptors are the functional link between the environment and the brain. The repair of sensory organs enables animals to continuously detect environmental stimuli. However, receptor cell turnover can affect sensory acuity by changing neural connectivity patterns. In zebrafish, two to four postsynaptic lateralis afferent axons converge into individual peripheral mechanosensory organs called neuromasts, which contain hair cell receptors of opposing planar polarity. Yet, each axon exclusively synapses with hair cells of identical polarity during development and regeneration to transmit unidirectional mechanical signals to the brain. The mechanism that governs this exceptionally accurate and resilient synaptic selectivity remains unknown. We show here that converging axons are mutually dependent for polarity-selective connectivity. If rendered solitary, these axons establish simultaneous functional synapses with hair cells of opposing polarities to transmit bidirectional mechanical signals. Remarkably, nonselectivity by solitary axons can be corrected upon the reintroduction of additional axons. Collectively, our results suggest that lateralis synaptogenesis is intrinsically nonselective and that interaxonal interactions continuously rectify mismatched synapses. This dynamic organization of neural connectivity may represent a general solution to maintain coherent synaptic transmission from sensory organs undergoing frequent variations in the number and spatial distribution of receptor cells. PMID:25484295
Synaptic Vesicle Populations in Saccular Hair Cells Reconstructed by Electron Tomography
David Lenzi; Jonathan W. Runyeon; John Crum; Mark H. Ellisman; William M. Roberts
We used electron tomography to map the three-dimensional architecture of the ribbon-class afferent synapses in frog sac- cular hair cells. The synaptic body (SB) at each synapse was nearly spherical (468 6 65 nm diameter; mean 6 SD) and was covered by a monolayer of synaptic vesicles (34.3 nm diameter; 8.8% coefficient of variation), many of them tethered to it
Functional Synaptic Projections onto Subplate Neurons in Neonatal Rat Somatosensory Cortex
Ileana L. Hanganu; Werner Kilb; Heiko J. Luhmann
Subplate neurons (SPn) play an important role in the formation of thalamocortical connections during early development and show glutamatergic and GABAergic spontaneous synaptic ac- tivity. We characterized these synaptic inputs by performing whole-cell recordings from SPn in somatosensory cortical slices of postnatal day 0-3 rats. At -70 mV, electrical stimulation of the thalamocortical afferents elicited in 68% of the SPn
Brain-derived neurotrophic factor drives the changes in excitatory synaptic transmission in the rat superficial dorsal horn that follow sciatic nerve injury
Lu, Van B; Biggs, James E; Stebbing, Martin J; Balasubramanyan, Sridhar; Todd, Kathryn G; Lai, Aaron Y; Colmers, William F; Dawbarn, David; Ballanyi, Klaus; Smith, Peter A
Peripheral nerve injury can promote neuropathic pain. The basis of the 'central sensitization' that underlies this often intractable condition was investigated using 14–20-day chronic constriction injury (CCI) of the sciatic nerve of 20-day-old rats followed by electrophysiological analysis of acutely isolated spinal cord slices. In addition, defined-medium organotypic spinal cord slice cultures were exposed for 5–6 days to brain-derived neurotrophic factor (BDNF, 200 ng ml?1) or to medium conditioned with activated microglia (aMCM). Since microglial activation is an early consequence of CCI, the latter manipulation allowed us to model the effect of peripheral nerve injury on the dorsal horn in vitro. Using whole-cell recording from superficial dorsal horn neurons, we found that both BDNF and CCI increased excitatory synaptic drive to putative excitatory 'radial delay' neurons and decreased synaptic excitation of inhibitory 'tonic islet/central' neurons. BDNF also attenuated synaptic excitation of putative GABAergic neurons identified by glutamic acid decarboxylase (GAD) immunoreactivity. Intrinsic neuronal properties (rheobase, input resistance and action potential discharge rates) were unaffected. Exposure of organotypic cultures to either BDNF or aMCM increased overall excitability of the dorsal horn, as seen by increased cytoplasmic Ca2+ responses to 35 mm K+ as monitored by confocal Fluo-4AM imaging. The effect of aMCM was attenuated by the recombinant BDNF binding protein TrkBd5 and the effect of BDNF persisted when GABAergic inhibition was blocked with SR95531. These findings suggest that CCI enhances excitatory synaptic drive to excitatory neurons but decreases that to inhibitory neurons. Both effects are mediated by nerve injury-induced release of BDNF from microglia. PMID:19124536
Specificity of afferent synapses onto plane-polarized hair cells in the posterior lateral line of the zebrafish
Nagiel, Aaron; Andor-Ardó, Daniel
The proper wiring of the vertebrate brain represents an extraordinary developmental challenge, requiring billions of neurons to select their appropriate synaptic targets. In view of this complexity, simple vertebrate systems provide necessary models for understanding how synaptic specificity arises. The posterior lateral-line organ of larval zebrafish consists of polarized hair cells organized in discrete clusters known as neuromasts. Here we show that each afferent neuron of the posterior lateral line establishes specific contacts with hair cells of the same hair-bundle polarity. We quantify this specificity by modeling the neuron as a biased selector of hair-cell polarity and find evidence for bias from as early as 2.5 days post-fertilization. More than half of the neurons form contacts on multiple neuromasts, but the innervated organs are spatially consecutive and the polarity preference is consistent. Using a novel reagent for correlative electron microscopy, HRP-mCherry, we show that these contacts are indeed afferent synapses bearing vesicle-loaded synaptic ribbons. Moreover, afferent neurons reassume their biased innervation pattern after hair-cell ablation and regeneration. By documenting specificity in the pattern of neuronal connectivity during development and in the context of organ regeneration, these results establish the posterior lateral-line organ as a vertebrate system for the in vivo study of synaptic target selection. PMID:18716202
Topoisomerase 1 inhibition reversibly impairs synaptic function
Mabb, Angela M.; Kullmann, Paul H. M.; Twomey, Margaret A.; Miriyala, Jayalakshmi; Philpot, Benjamin D.; Zylka, Mark J.
Topotecan is a topoisomerase 1 (TOP1) inhibitor that is used to treat various forms of cancer. We recently found that topotecan reduces the expression of multiple long genes, including many neuronal genes linked to synapses and autism. However, whether topotecan alters synaptic protein levels and synapse function is currently unknown. Here we report that in primary cortical neurons, topotecan depleted synaptic proteins that are encoded by extremely long genes, including Neurexin-1, Neuroligin-1, Cntnap2, and GABAA?3. Topotecan also suppressed spontaneous network activity without affecting resting membrane potential, action potential threshold, or neuron health. Topotecan strongly suppressed inhibitory neurotransmission via pre- and postsynaptic mechanisms and reduced excitatory neurotransmission. The effects on synaptic protein levels and inhibitory neurotransmission were fully reversible upon drug washout. Collectively, our findings suggest that TOP1 controls the levels of multiple synaptic proteins and is required for normal excitatory and inhibitory synaptic transmission. PMID:25404338
Regulation of AMPA Receptor Trafficking and Synaptic Plasticity
Anggono, Victor; Huganir, Richard L.
AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Dynamic changes in neuronal synaptic efficacy, termed synaptic plasticity, are thought to underlie information coding and storage in learning and memory. One major mechanism that regulates synaptic strength involves the tightly regulated trafficking of AMPARs into and out of synapses. The life cycle of AMPARs from their biosynthesis, membrane trafficking and synaptic targeting to their degradation are controlled by a series of orchestrated interactions with numerous intracellular regulatory proteins. Here we review recent progress made towards the understanding the regulation of AMPAR trafficking, focusing on the roles of several key intracellular AMPAR interacting proteins. PMID:22217700
Onset Coding Is Degraded in Auditory Nerve Fibers from Mutant Mice Lacking Synaptic Ribbons
Buran, Bradley N.
Synaptic ribbons, found at the presynaptic membrane of sensory cells in both ear and eye, have been implicated in the vesicle-pool dynamics of synaptic transmission. To elucidate ribbon function, we characterized the ...
Active Hippocampal Networks Undergo Spontaneous Synaptic Modification
Tsukamoto-Yasui, Masako; Sasaki, Takuya; Matsumoto, Wataru; Hasegawa, Ayako; Toyoda, Takeshi; Usami, Atsushi; Kubota, Yuichi; Ochiai, Taku; Hori, Tomokatsu; Matsuki, Norio; Ikegaya, Yuji
The brain is self-writable; as the brain voluntarily adapts itself to a changing environment, the neural circuitry rearranges its functional connectivity by referring to its own activity. How the internal activity modifies synaptic weights is largely unknown, however. Here we report that spontaneous activity causes complex reorganization of synaptic connectivity without any external (or artificial) stimuli. Under physiologically relevant ionic conditions, CA3 pyramidal cells in hippocampal slices displayed spontaneous spikes with bistable slow oscillations of membrane potential, alternating between the so-called UP and DOWN states. The generation of slow oscillations did not require fast synaptic transmission, but their patterns were coordinated by local circuit activity. In the course of generating spontaneous activity, individual neurons acquired bidirectional long-lasting synaptic modification. The spontaneous synaptic plasticity depended on a rise in intracellular calcium concentrations of postsynaptic cells, but not on NMDA receptor activity. The direction and amount of the plasticity varied depending on slow oscillation patterns and synapse locations, and thus, they were diverse in a network. Once this global synaptic refinement occurred, the same neurons now displayed different patterns of spontaneous activity, which in turn exhibited different levels of synaptic plasticity. Thus, active networks continuously update their internal states through ongoing synaptic plasticity. With computational simulations, we suggest that with this slow oscillation-induced plasticity, a recurrent network converges on a more specific state, compared to that with spike timing-dependent plasticity alone. PMID:18043757
Destruction of inferior olive induces rapid depression in synaptic action of cerebellar Purkinje cells
Masao Ito; Naoko Nisimaru; Katsuei Shibuki
THE climbing fibre afferents (CFAs) are a structure unique to the cerebellar cortex; they originate, presumably solely, from the inferior olive (IO) and make an extensive, excitatory synaptic contact with dendrites of cerebellar Purkinje cells (P cells)1. The importance of the CFAs in cerebellar functions has been emphasised in connection with the learning process which may occur in the cerebellar
Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial Vulnerability
Synaptic mitochondria are essential for maintaining calcium homeostasis and producing ATP, processes vital for neuronal integrity and synaptic transmission. Synaptic mitochondria exhibit increased oxidative damage during aging and are more vulnerable to calcium insult than nonsynaptic mitochondria. Why synaptic mitochondria are specifically more susceptible to cumulative damage remains to be determined. In this study, the generation of a super-SILAC mix that served as an appropriate internal standard for mouse brain mitochondria mass spectrometry based analysis allowed for the quantification of the proteomic differences between synaptic and nonsynaptic mitochondria isolated from 10-month-old mice. We identified a total of 2260 common proteins between synaptic and nonsynaptic mitochondria of which 1629 were annotated as mitochondrial. Quantitative proteomic analysis of the proteins common between synaptic and nonsynaptic mitochondria revealed significant differential expression of 522 proteins involved in several pathways including oxidative phosphorylation, mitochondrial fission/fusion, calcium transport, and mitochondrial DNA replication and maintenance. In comparison to nonsynaptic mitochondria, synaptic mitochondria exhibited increased age-associated mitochondrial DNA deletions and decreased bioenergetic function. These findings provide insights into synaptic mitochondrial susceptibility to damage. PMID:24708184
Quantitative proteomics of synaptic and nonsynaptic mitochondria: insights for synaptic mitochondrial vulnerability.
Stauch, Kelly L; Purnell, Phillip R; Fox, Howard S
Synaptic mitochondria are essential for maintaining calcium homeostasis and producing ATP, processes vital for neuronal integrity and synaptic transmission. Synaptic mitochondria exhibit increased oxidative damage during aging and are more vulnerable to calcium insult than nonsynaptic mitochondria. Why synaptic mitochondria are specifically more susceptible to cumulative damage remains to be determined. In this study, the generation of a super-SILAC mix that served as an appropriate internal standard for mouse brain mitochondria mass spectrometry based analysis allowed for the quantification of the proteomic differences between synaptic and nonsynaptic mitochondria isolated from 10-month-old mice. We identified a total of 2260 common proteins between synaptic and nonsynaptic mitochondria of which 1629 were annotated as mitochondrial. Quantitative proteomic analysis of the proteins common between synaptic and nonsynaptic mitochondria revealed significant differential expression of 522 proteins involved in several pathways including oxidative phosphorylation, mitochondrial fission/fusion, calcium transport, and mitochondrial DNA replication and maintenance. In comparison to nonsynaptic mitochondria, synaptic mitochondria exhibited increased age-associated mitochondrial DNA deletions and decreased bioenergetic function. These findings provide insights into synaptic mitochondrial susceptibility to damage. PMID:24708184
Postsynaptic hyperpolarization increases the strength of AMPA-mediated synaptic transmission at large synapses between mossy fibers and CA3 pyramidal cells.
Berretta, N; Rossokhin, A V; Kasyanov, A M; Sokolov, M V; Cherubini, E; Voronin, L L
In chemical synapses information flow is polarized. However, the postsynaptic cells can affect transmitter release via retrograde chemical signaling. Here we explored the hypothesis that, in large synapses, having large synaptic cleft resistance, transmitter release can be enhanced by electrical (ephaptic) signaling due to depolarization of the presynaptic release site induced by the excitatory postsynaptic current itself. The hypothesis predicts that, in such synapses, postsynaptic hyperpolarization would increase response amplitudes "supralinearly", i.e. stronger than predicted from the driving force shift. We found supralinear increases in the amplitude of minimal excitatory postsynaptic potential (EPSP) during hyperpolarization of CA3 pyramidal neurons. Failure rate, paired-pulse facilitation, coefficient of variation of the EPSP amplitude and EPSP quantal content were also modified. The effects were especially strong on mossy fiber EPSPs (MF-EPSPs) mediated by the activation of large synapses and identified pharmacologically or by their kinetics. The effects were weaker on commissural fiber EPSPs mediated by smaller and more remote synapses. Even spontaneous membrane potential fluctuations were associated with supralinear MF-EPSP increases and failure rate reduction. The results suggest the existence of a novel mechanism for retrograde control of synaptic efficacy from postsynaptic membrane potential and are consistent with the ephaptic feedback hypothesis. PMID:10974312
Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression
Bagot, Rosemary C.; Parise, Eric M.; Peńa, Catherine J.; Zhang, Hong-Xing; Maze, Ian; Chaudhury, Dipesh; Persaud, Brianna; Cachope, Roger; Bolańos-Guzmán, Carlos A.; Cheer, Joseph; Deisseroth, Karl; Han, Ming-Hu; Nestler, Eric J.
Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression. PMID:25952660
Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression.
Bagot, Rosemary C; Parise, Eric M; Peńa, Catherine J; Zhang, Hong-Xing; Maze, Ian; Chaudhury, Dipesh; Persaud, Brianna; Cachope, Roger; Bolańos-Guzmán, Carlos A; Cheer, Joseph; Deisseroth, Karl; Han, Ming-Hu; Nestler, Eric J
Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression. PMID:25952660
The cutaneous intrinsic visceral afferent nervous system: A new model for acupuncture analgesia
Morry Silberstein
The mechanism of acupuncture, whilst not known with certainty, has previously been considered to be stimulatory. A novel hypothesis is presented here in which C fiber tactile afferent axons bifurcate at acupuncture points and then diverge, running along acupuncture meridians, to subsequently communicate with Merkel cells. It is proposed that acupuncture disrupts the bifurcation of these axons, preventing neural transmission
Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder
Lee, P H; Perlis, R H; Jung, J-Y; Byrne, E M; Rueckert, E; Siburian, R; Haddad, S; Mayerfeld, C E; Heath, A C; Pergadia, M L; Madden, P A F; Boomsma, D I; Penninx, B W; Sklar, P; Martin, N G; Wray, N R; Purcell, S M; Smoller, J W
Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10?4). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD. PMID:23149448
Temperature differentially facilitates spontaneous but not evoked glutamate release from cranial visceral primary afferents.
Fawley, Jessica A; Hofmann, Mackenzie E; Largent-Milnes, Tally M; Andresen, Michael C
Temperature is fundamentally important to all biological functions including synaptic glutamate release. Vagal afferents from the solitary tract (ST) synapse on second order neurons in the nucleus of the solitary tract, and glutamate release at this first central synapse controls autonomic reflex function. Expression of the temperature-sensitive Transient Receptor Potential Vanilloid Type 1 receptor separates ST afferents into C-fibers (TRPV1+) and A-fibers (TRPV1-). Action potential-evoked glutamate release is similar between C- and A-fiber afferents, but TRPV1 expression facilitates a second form of synaptic glutamate release in C-fibers by promoting substantially more spontaneous glutamate release. The influence of temperature on different forms of glutamate release is not well understood. Here we tested how temperature impacts the generation of evoked and spontaneous release of glutamate and its relation to TRPV1 expression. In horizontal brainstem slices of rats, activation of ST primary afferents generated synchronous evoked glutamate release (ST-eEPSCs) at constant latency whose amplitude reflects the probability of evoked glutamate release. The frequency of spontaneous EPSCs in these same neurons measured the probability of spontaneous glutamate release. We measured both forms of glutamate from each neuron during ramp changes in bath temperature of 4-5°C. Spontaneous glutamate release from TRPV1+ closely tracked with these thermal changes indicating changes in the probability of spontaneous glutamate release. In the same neurons, temperature changed axon conduction registered as latency shifts but ST-eEPSC amplitudes were constant and independent of TRPV1 expression. These data indicate that TRPV1-operated glutamate release is independent of action potential-evoked glutamate release in the same neurons. Together, these support the hypothesis that evoked and spontaneous glutamate release originate from two pools of vesicles that are independently modulated and are distinct processes. PMID:25992717
Inhibitory Interneurons That Express GFP in the PrP-GFP Mouse Spinal Cord Are Morphologically Heterogeneous, Innervated by Several Classes of Primary Afferent and Include Lamina I Projection Neurons among Their Postsynaptic Targets.
Ganley, Robert P; Iwagaki, Noboru; Del Rio, Patricia; Baseer, Najma; Dickie, Allen C; Boyle, Kieran A; Polgár, Erika; Watanabe, Masahiko; Abraira, Victoria E; Zimmerman, Amanda; Riddell, John S; Todd, Andrew J
The superficial dorsal horn of the spinal cord contains numerous inhibitory interneurons, which regulate the transmission of information perceived as touch, pain, or itch. Despite the importance of these cells, our understanding of their roles in the neuronal circuitry is limited by the difficulty in identifying functional populations. One group that has been identified and characterized consists of cells in the mouse that express green fluorescent protein (GFP) under control of the prion protein (PrP) promoter. Previous reports suggested that PrP-GFP cells belonged to a single morphological class (central cells), received inputs exclusively from unmyelinated primary afferents, and had axons that remained in lamina II. However, we recently reported that the PrP-GFP cells expressed neuronal nitric oxide synthase (nNOS) and/or galanin, and it has been shown that nNOS-expressing cells are more diverse in their morphology and synaptic connections. We therefore used a combined electrophysiological, pharmacological, and anatomical approach to reexamine the PrP-GFP cells. We provide evidence that they are morphologically diverse (corresponding to "unclassified" cells) and receive synaptic input from a variety of primary afferents, with convergence onto individual cells. We also show that their axons project into adjacent laminae and that they target putative projection neurons in lamina I. This indicates that the neuronal circuitry involving PrP-GFP cells is more complex than previously recognized, and suggests that they are likely to have several distinct roles in regulating the flow of somatosensory information through the dorsal horn. PMID:25972186
Nicotine and Synaptic Plasticity in Prefrontal Cortex
NSDL National Science Digital Library
Daniel S. McGehee (University of Chicago; Department of Anesthesia and Critical Care REV)
Nicotinic receptor activation enhances working memory and attention. The prefrontal cortex is a key brain area involved in working memory, and plasticity of excitatory synaptic transmission within the cortex is likely an important cellular mechanism of memory. A recent study has explored the cellular and synaptic basis of nicotine's effects on excitability within the prefrontal cortex. The findings suggest that nicotine enhances inhibitory synaptic inputs to layer V pyramidal cells, which suppresses induction of long-term potentiation (LTP). This inhibitory effect can be overcome by stimulating the pyramidal cells in bursts, which suggests a modification in the signal-to-noise ratio for synaptic input. Thus, the impact of strong stimuli on working memory would be enhanced when combined with nicotinic receptor activity. These findings may lead to novel and more effective treatments for memory disorders.
GABA-mediated synaptic inhibition of projection neurons in the antennal lobes of the sphinx moth, Manduca sexta
Brian Waldrop; Thomas A. Christensen; John G. Hildebrand
1.Responses of neurons in the antennal lobe (AL) of the mothManduca sexta to stimulation of the ipsilateral antenna by odors consist of excitatory and inhibitory synaptic potentials (Fig. 2A). Stimulation of primary afferent fibers by electrical shock of the antennal nerve causes a characteristic IPSP-EPSP synaptic response in AL projection neurons (Fig. 2B).2.The IPSP in projection neurons reverses below the
Reliable synaptic connections between pairs of excitatory layer 4 neurones within a single 'barrel' of developing rat somatosensory cortex.
Feldmeyer, D; Egger, V; Lubke, J; Sakmann, B
1. Dual whole-cell recordings were made from pairs of synaptically coupled excitatory neurones in the 'barrel field' in layer (L) 4 in slices of young (postnatal day 12-15) rat somatosensory cortex. The majority of interconnected excitatory neurones were spiny stellate cells with an asymmetrical dendritic arborisation largely confined to a single barrel. The remainder were star pyramidal cells with a prominent apical dendrite terminating in L2/3 without forming a tuft. 2. Excitatory synaptic connections were examined between 131 pairs of spiny L4 neurones. Single presynaptic action potentials evoked unitary EPSPs with a peak amplitude of 1.59 +/- 1.51 mV (mean +/- s. d.), a latency of 0.92 +/- 0.35 ms, a rise time of 1.53 +/- 0.46 ms and a decay time constant of 17.8 +/- 6.3 ms. 3. At 34-36 C, the coefficient of variation (c.v.) of the unitary EPSP amplitude was 0. 37 +/- 0.16 and the percentage of failures to evoke an EPSP was 5.3 +/- 7.8 %. The c.v. and failure rate decreased with increasing amplitude of the unitary EPSP. 4. Postsynaptic glutamate receptors in spiny L4 neurones were of the AMPA and NMDA type. At -60 mV in the presence of 1 mM Mg2+, NMDA receptors contributed 39.3 +/- 12.5 % to the EPSP integral. In Mg2+-free solution, the NMDA receptor/AMPA receptor ratio of the EPSC was 0.86 +/- 0.64. 5. The number of putative synaptic contacts established by the projection neurone with the target neurone varied between two and five with a mean of 3.4 +/- 1.0 (n = 11). Synaptic contacts were exclusively found in the barrel in which the cell pair was located and were preferentially located on secondary to quarternary dendritic branches. Their mean geometric distance from the soma was 68.8 +/- 37.4 microm (range, 33.4-168.0 microm). The number of synaptic contacts and mean EPSP amplitude showed no significant correlation. 6. The results suggest that in L4 of the barrel cortex synaptic transmission between spiny neurones is largely restricted to a single barrel. The connections are very reliable, probably due to a high release probability, and have a high efficacy because of the compact structure of the dendrites and axons of spiny neurones. Intrabarrel connections thus function to amplify and distribute the afferent thalamic activity in the vertical directions of a cortical column. PMID:10562343
Projection of cat jaw muscle spindle afferents related to intrafusal fibre influence.
Taylor, A; Durbaba, R; Rodgers, J F
1. A method of classification of muscle spindle afferents using succinylcholine (SCh) and ramp stretches has recently been described, which appears to estimate separately the strength of influence of bag1 (b1) and of bag2 (b2) intrafusal fibres. Increase in dynamic difference (delta DD) indicates b1 influence whilst increase in initial frequency (delta IF) indicates b2 influence. The significance of this classification has now been examined by correlation with the strength of synaptic projection of jaw muscle spindle afferents to the fifth motor nucleus (MotV) and the supratrigeminal region (STR) in anaesthetized cats. 2. Projection strength was estimated by computing the extracellular focal synaptic potential (FSP) from spike-triggered averages of 1024 sweeps at 100 microns intervals along tracks through STR and MotV. Trigger pulses were derived from spindle afferent cell bodies of the jaw-closer muscles recorded in the mesencephalic trigeminal nucleus, and characterized by the effect of SCh on their responses to ramp-and-hold stretches. 3. The maximum size of FSPs in tracks traversing STR and MotV ranged from 2.08 to 36.99 microV with a mean of 7.55 microV. The amplitudes were bimodally distributed into roughly equal-sized groups with high and low amplitude FSPs. 4. Mean values of delta IF were significantly greater for the group with large FSPs than for those with small FSPs. There were no significant differences in delta DD. FSP amplitude was significantly positively correlated with delta IF, but not with delta DD. 5. Spindle afferents with high values of FSP amplitude in MotV had a wide range of values of delta DD (b1b2c and b2c groups), while units with large FSPs in STR were all in the b2c category. Some evidence is presented to indicate that this reflects a preferential projection of secondary afferents to the STR. 6. For those units with projection to both STR and to MotV, there was a significant positive correlation between FSP amplitude in the two nuclei. 7. These results indicate that the extent of the b2 influence on spindle afferents predicts the central projection strength better than does the b1 influence. This finding is discussed from the viewpoint of possible developmental and functional issues. PMID:8229855
Research progress on the age-related changes in proteins of the synaptic active zone
Xiang-Dong Xiong; Gui-Hai Chen
Neurotransmitter release during synaptic transmission is mediated by the presynaptic active zone. Multiple protein components at the active zone region interact to regulate docking, priming and fusion of the synaptic vesicles with the presynaptic membrane to maintain normal neurotransmitter release. This review discusses research progress in questions of protein transcript and expression pattern changes at the synaptic active zone related
Modulation of synaptic transmission and excitation-contraction coupling in the opener muscle of the crayfish, Astacus leptodactylus, by 5-hydroxytryptamine and octopamine.
Fischer, L; Florey, E
The modulatory actions of 5-hydroxytryptamine (5-HT) and octopamine (OA) were investigated in the opener nerve-muscle preparation of the crayfish, Astacus leptodactylus. Membrane resistance and resting potential were unaltered by 5-HT and OA at concentrations up to 2.5 X 10(-5) M; but EPSP-amplitudes were increased, up to 3-fold by OA and up to 18-fold by 5-HT. The lowest effective concentration was 2.5 X 10(-9) M; a maximal effect was produced at 2.5 X 10(-6) M. The effect was reversible only after prolonged washing. The enhancement of EPSPs by 5-HT or OA is due to an increased amplitude of the synaptic current; the current duration is not altered. The facilitation ratio (ratio of amplitudes of a pair of EPSPs) is not significantly affected by 5-HT or OA despite the often enormous increase of the absolute EPSP-amplitudes. The modulatory action also affects the excitation-contraction (e-c) coupling process: the effectiveness of e-c coupling was increased 7.4-fold by 5-HT (2.5 X 10(-6) M) and 18.7-fold by OA (5 X 10(-6) M). The threshold potential of e-c coupling was not affected. PMID:6300277
Enhanced synaptic inhibition disrupts the efferent code of cerebellar Purkinje neurons in leaner Cav2.1 Ca 2+ channel mutant mice.
Ovsepian, Saak V; Friel, David D
Cerebellar Purkinje cells (PCs) encode afferent information in the rate and temporal structure of their spike trains. Both spontaneous firing in these neurons and its modulation by synaptic inputs depend on Ca(2+) current carried by Ca(v)2.1 (P/Q) type channels. Previous studies have described how loss-of-function Ca(v)2.1 mutations affect intrinsic excitability and excitatory transmission in PCs. This study examines the effects of the leaner mutation on fast GABAergic transmission and its modulation of spontaneous firing in PCs. The leaner mutation enhances spontaneous synaptic inhibition of PCs, leading to transitory reductions in PC firing rate and increased spike rate variability. Enhanced inhibition is paralleled by an increase in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) measured under voltage clamp. These differences are abolished by tetrodotoxin, implicating effects of the mutation on spike-induced GABA release. Elevated sIPSC frequency in leaner PCs is not accompanied by increased mean firing rate in molecular layer interneurons, but IPSCs evoked in PCs by direct stimulation of these neurons exhibit larger amplitude, slower decay rate, and a higher burst probability compared to wild-type PCs. Ca(2+) release from internal stores appears to be required for enhanced inhibition since differences in sIPSC frequency and amplitude in leaner and wild-type PCs are abolished by thapsigargin, an ER Ca(2+) pump inhibitor. These findings represent the first account of the functional consequences of a loss-of-function P/Q channel mutation on PC firing properties through altered GABAergic transmission. Gain in synaptic inhibition shown here would compromise the fidelity of information coding in these neurons and may contribute to impaired cerebellar function resulting from loss-of function mutations in the Ca(V)2.1 channel gene. PMID:20845003
Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans
Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M.J.M.; Pietrobon, Daniela
Familial hemiplegic migraine type 1 (FHM1) is caused by gain-of-function mutations in CaV2.1 (P/Q-type) Ca2+ channels. Knockin (KI) mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD) in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca2+ dependence of the excitatory postsynaptic current were similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca2+ influx at voltages sub-threshold for action potential generation. PMID:25741235
Activation of presynaptic GABA(B(1a,2)) receptors inhibits synaptic transmission at mammalian inhibitory cholinergic olivocochlear-hair cell synapses.
Wedemeyer, Carolina; Zorrilla de San Martín, Javier; Ballestero, Jimena; Gómez-Casati, María Eugenia; Torbidoni, Ana Vanesa; Fuchs, Paul A; Bettler, Bernhard; Elgoyhen, Ana Belén; Katz, Eleonora
The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca(2+)-permeable postsynaptic ?9?10 nicotinic receptors coupled to the opening of hyperpolarizing Ca(2+)-activated small-conductance type 2 (SK2)K(+) channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABA(B(1a,2)) receptors [GABA(B(1a,2))Rs] that downregulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABA(B)Rs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABA(B1)-GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABA(B1a) isoform selectively inhibits release at efferent cholinergic synapses. PMID:24068816
Synaptic plasticity along the sleep–wake cycle: Implications for epilepsy
Rodrigo N. Romcy-Pereira; Joăo P. Leite; Norberto Garcia-Cairasco
Activity-dependent changes in synaptic efficacy (i.e., synaptic plasticity) can alter the way neurons communicate and process information as a result of experience. Synaptic plasticity mechanisms involve both molecular and structural modifications that affect synaptic functioning, either enhancing or depressing neuronal transmission. They include redistribution of postsynaptic receptors, activation of intracellular signaling cascades, and formation\\/retraction of dendritic spines, among others. During
Distinct roles for Cav2.1-2.3 in activity-dependent synaptic dynamics.
Ricoy, Ulises M; Frerking, Matthew E
Synaptic transmission throughout most of the CNS is steeply dependent on presynaptic calcium influx through the voltage-gated calcium channels Cav2.1-Cav2.3. In addition to triggering exocytosis, this calcium influx also recruits short-term synaptic plasticity. During the complex patterns of presynaptic activity that occur in vivo, several forms of plasticity combine to generate a synaptic output that is dynamic, in which the size of a given excitatory postsynaptic potential (EPSP) in response to a given spike depends on the short-term history of presynaptic activity. It remains unclear whether the different Cav2 channels play distinct roles in defining these synaptic dynamics and, if so, under what conditions different Cav2 family members most effectively determine synaptic output. We examined these questions by measuring the effects of calcium channel-selective toxins on synaptic transmission at the Schaffer collateral synapse in hippocampal slices from adult mice in response to both low-frequency stimulation and complex stimulus trains derived from in vivo recordings. Blockade of Cav2.1 had a greater inhibitory effect on synaptic transmission during low-frequency components of the stimulus train than on synaptic transmission during high-frequency components of the train, indicating that Cav2.1 had a greater fractional contribution to synaptic transmission at low frequencies than at high frequencies. Relative to Cav2.1, Cav2.2 had a disproportionately reduced contribution to synaptic transmission at frequencies >20 Hz, while Cav2.3 had a disproportionately increased contribution to synaptic transmission at frequencies >1 Hz. These activity-dependent effects of different Cav2 family members shape the filtering characteristics of GABAB receptor-mediated presynaptic inhibition. Thus different Cav2 channels vary in their coupling to synaptic transmission over different frequency ranges, with consequences for the frequency tuning of both synaptic dynamics and presynaptic neuromodulation. PMID:24523520
Piezo2 expression in corneal afferent neurons.
Bron, Romke; Wood, Rhiannon J; Brock, James A; Ivanusic, Jason J
Recently, a novel class of mechanically sensitive channels has been identified and have been called Piezo channels. In this study, we explored Piezo channel expression in sensory neurons supplying the guinea pig corneal epithelium, which have well-defined modalities in this species. We hypothesized that a proportion of corneal afferent neurons express Piezo2, and that these neurons are neurochemically distinct from corneal polymodal nociceptors or cold-sensing neurons. We used a combination of retrograde tracing to identify corneal afferent neurons and double label in situ hybridization and/or immunohistochemistry to determine their molecular and/or neurochemical profile. We found that Piezo2 expression occurs in ?26% of trigeminal ganglion neurons and 30% of corneal afferent neurons. Piezo2 corneal afferent neurons are almost exclusively non-calcitonin gene-related peptide (CGRP)-immunoreactive (-IR), medium- to large-sized neurons that are NF200-IR, suggesting they are not corneal polymodal nociceptors. There was no coexpression of Piezo2 and transient receptor potential cation channel subfamily M member 8 (TRPM8) transcripts in any corneal afferent neurons, further suggesting that Piezo2 is not expressed in corneal cold-sensing neurons. We also noted that TRPM8-IR or CGRP-IR corneal afferent neurons are almost entirely small and lack NF200-IR. Piezo2 expression occurs in a neurochemically distinct subpopulation of corneal afferent neurons that are not polymodal nociceptors or cold-sensing neurons, and is likely confined to a subpopulation of pure mechano-nociceptors in the cornea. This provides the first evidence in an in vivo system that Piezo2 is a strong candidate for a channel that transduces noxious mechanical stimuli. PMID:24549492
Differential Synaptology of vGluT2-containing thalamostriatal afferents between the patch and matrix compartments in rats
Raju, Dinesh V.; Shah, Deep J.; Wright, Terrence M.; Hall, Randy A.; Smith, Yoland
The striatum is divided into two compartments named the patch (or striosome) and matrix. Although these two compartments can be differentiated by their neurochemical content or afferent and efferent projections, the synaptology of inputs to these striatal regions remains poorly characterized. Using the vesicular glutamate transporters vGluT1 and vGluT2, as markers of corticostriatal and thalamostriatal projections, respectively, we demonstrate a differential pattern of synaptic connections of these two pathways between the patch and matrix compartments. We also demonstrate that the majority of vGluT2-immunolableled axon terminals form axo-spinous synapses, suggesting that thalamic afferents, like corticostriatal inputs, terminate preferentially onto spines in the striatum. Within both compartments more than 90% of vGluT1-containing terminals formed axo-spinous synapses, whereas 87% of vGluT2-positive terminals within the patch innervated dendritic spines, but only 55% did so in the matrix. To further characterize the source of thalamic inputs that could account for the increase in axo-dendritic synapses in the matrix, we undertook an electron microscopic analysis of the synaptology of thalamostriatal afferents to the matrix compartments from specific intralaminar, midline, relay, and associative thalamic nuclei in rats. Approximately 95% of PHA-L-labeled terminals from the central lateral, midline, mediodorsal, lateral dorsal, anteroventral and ventral anterior/ventral lateral nuclei formed axo-spinous synapses, a pattern reminiscent of corticostriatal afferents, but strikingly different from thalamostriatal projections arising from the parafascicular nucleus (PF), which terminate onto dendritic shafts. These findings provide the first evidence for a differential pattern of synaptic organization of thalamostriatal glutamatergic inputs to the patch and matrix compartments. Furthermore, they demonstrate that the PF is the sole source of significant axo-dendritic thalamic inputs to striatal projection neurons. These observations pave the way for understanding differential regulatory mechanisms of striatal outflow from the patch and matrix compartments by thalamostriatal afferents. PMID:16977615
The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing
Aksoy-Aksel, Ayla; Manahan-Vaughan, Denise
In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing. PMID:23986697
Transcriptional coupling of synaptic transmission and energy metabolism: Role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons
Dhar, Shilpa S.; Liang, Huan Ling; Wong-Riley, Margaret T. T.
SUMMARY Neuronal activity is highly dependent on energy metabolism; yet, the two processes have traditionally been regarded as independently regulated at the transcriptional level. Recently, we found that the same transcription factor, nuclear respiratory factor 1 (NRF-1) co-regulates an important energy-generating enzyme, cytochrome c oxidase, as well as critical subunits of glutamatergic receptors. The present study tests our hypothesis that the co-regulation extends to the next level of glutamatergic synapses, namely, neuronal nitric oxide synthase, which generates nitric oxide as a downstream signaling molecule. Using in silico analysis, electrophoretic mobility shift assay, chromatin immunoprecipitation, promoter mutations, and NRF-1 silencing, we documented that NRF-1 functionally bound to Nos1, but not Nos2 (inducible) and Nos3 (endothelial) gene promoters. Both COX and Nos1 transcripts were up-regulated by depolarizing KCl treatment and down-regulated by TTX-mediated impulse blockade in neurons. However, NRF-1 silencing blocked the up-regulation of both Nos1 and COX induced by KCl depolarization, and over-expression of NRF-1 rescued both Nos1 and COX transcripts downregulated by TTX. These findings are consistent with our hypothesis that synaptic neuronal transmission and energy metabolism are tightly coupled at the molecular level. PMID:19615412
Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord
Wang, Z.; Li, L-Y.; Taylor, M. T.; Wright, D. E.; Frank, E.
Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are largely unknown. In this study, we report that embryonic over-expression of NT3 in muscles disrupts the development of these specific Ia-MN connections, utilizing transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic excitatory postsynaptic potentials evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia-MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit. PMID:17409232
Glutamate-like immunoreactivity in ascending spinofugal afferents to the rat periaqueductal grey.
Azkue, J J; Mateos, J M; Elezgarai, I; Benítez, R; Lázaro, E; Streit, P; Grandes, P
The midbrain periaqueductal gray is a key structure for the mediation of an integrated defence behaviour. Although a prominent role for glutamate in PAG mechanisms is supported by both behavioural and morphological studies, whether PAG afferents conveying somatosensory information constitute a source of glutamatergic input to the PAG remains unknown. Here, we have compared the projection pattern of orthogradely-labelled spinoannular fibres with the distribution of glutamate-like immunoreactivity in the PAG at the light microscopic level. Transaxonal labelling was observed throughout the whole rostrocaudal axis of the PAG except for the dorsolateral regions. Cell-processes and terminal-reminiscent puncta were strongly immunoreactive in all PAG regions, including the dorsolateral areas. To ascertain whether glutamate-immunoreactive puncta observed at light microscopy indeed constituted axon terminals of the spinoannular system, glutamate-like immunoreactivity was assessed in orthogradely-labelled synaptic terminals using a post-embedding immunogold procedure for electron microscopy. Quantitative analysis of gold particle densities revealed over twice as strong an immunoreactivity in anatomically-identified spinoannular axon terminals as in dendrites postsynaptic to them, perikarya and inhibitory Gray II synapses, as well as an over 5-fold heavier immunolabelling than in glial profiles. These findings reveal that glutamate is accumulated in synaptic terminals of the spinoannular system, supporting a neurotransmitter role for this acidic amino acid in spinofugal afferents to the PAG. PMID:9593831
Transneuronal tracing of central autonomic regions involved in cardiac sympathetic afferent reflex in rats.
Gao, Juan; Zhang, Feng; Sun, Hai-Jian; Liu, Tong-Yan; Ding, Lei; Kang, Yu-Ming; Zhu, Guo-Qing; Zhou, Ye-Bo
Stimulation of cardiac afferents (CA) increased sympathetic outflow and blood pressure. The goal of the current study is to determine the central autonomic nuclei involved in the regulation of cardiac sympathetic afferent reflex (CSAR) which has been proved in previously functional studies. Neuroanatomical method and pseudorabies virus (PRV) transynaptic retrograde trace technique will be performed to investigate the relationship between kidney and heart and the temporal order of the most PRV-labeled neurons in the central nervous system. Recombinant PRV expressing enhanced green fluorescence protein (EGFP) was injected into the left kidney of rats as a specific trans-synaptic retrograde tracer in neurons. After 2, 3, 4, 5, 6, 7, 8 or 9 days, brain, spinal cord and heart were collected for immunofluorescence staining. The temporal order of PRV labeled neurons was found in the ipsilateral intermediolateral nucleus (IML) of T8-T12 spinal segments on day 3; bilateral rostroventrolateral medulla (RVLM), paraventricular nucleus (PVN) and nucleus of the solitary tract (NTS) on day 4; and left and right ventricular walls and ventricular septum of the heart on day 9. In rats with renal denervation, no PRV-infected neurons or cardiomyocytes were found after PRV injection. In conclusion, PRV trans-synaptic retrograde trace confirms that CA, NTS, PVN, RVLM, IML and renal nerves do exist to be involved in the regulation of CSAR and there is a close relationship between heart and kidney. CA is mainly located in the left ventricular wall, right ventricular wall and ventricular septum. PMID:24819915
5,6-EET is released upon neuronal activity and induces mechanical pain hypersensitivity via TRPA1 on central afferent terminals.
Sisignano, Marco; Park, Chul-Kyu; Angioni, Carlo; Zhang, Dong Dong; von Hehn, Christian; Cobos, Enrique J; Ghasemlou, Nader; Xu, Zhen-Zhong; Kumaran, Vigneswara; Lu, Ruirui; Grant, Andrew; Fischer, Michael J M; Schmidtko, Achim; Reeh, Peter; Ji, Ru-Rong; Woolf, Clifford J; Geisslinger, Gerd; Scholich, Klaus; Brenneis, Christian
Epoxyeicosatrienoic acids (EETs) are cytochrome P450-epoxygenase-derived metabolites of arachidonic acid that act as endogenous signaling molecules in multiple biological systems. Here we have investigated the specific contribution of 5,6-EET to transient receptor potential (TRP) channel activation in nociceptor neurons and its consequence for nociceptive processing. We found that, during capsaicin-induced nociception, 5,6-EET levels increased in dorsal root ganglia (DRGs) and the dorsal spinal cord, and 5,6-EET is released from activated sensory neurons in vitro. 5,6-EET potently induced a calcium flux (100 nm) in cultured DRG neurons that was completely abolished when TRPA1 was deleted or inhibited. In spinal cord slices, 5,6-EET dose dependently enhanced the frequency, but not the amplitude, of spontaneous EPSCs (sEPSCs) in lamina II neurons that also responded to mustard oil (allyl isothiocyanate), indicating a presynaptic action. Furthermore, 5,6-EET-induced enhancement of sEPSC frequency was abolished in TRPA1-null mice, suggesting that 5,6-EET presynaptically facilitated spinal cord synaptic transmission by TRPA1. Finally, in vivo intrathecal injection of 5,6-EET caused mechanical allodynia in wild-type but not TRPA1-null mice. We conclude that 5,6-EET is synthesized on the acute activation of nociceptors and can produce mechanical hypersensitivity via TRPA1 at central afferent terminals in the spinal cord. PMID:22553041
Inhibition of excitatory synaptic transmission in hippocampal neurons by levetiracetam involves Zn˛?-dependent GABA type A receptor-mediated presynaptic modulation.
Wakita, Masahito; Kotani, Naoki; Kogure, Kyuya; Akaike, Norio
Levetiracetam (LEV) is an antiepileptic drug with a unique but as yet not fully resolved mechanism of action. Therefore, by use of a simplified rat-isolated nerve-bouton preparation, we have investigated how LEV modulates glutamatergic transmission from mossy fiber terminals to hippocampal CA3 neurons. Action potential-evoked excitatory postsynaptic currents (eEPSCs) were recorded using a conventional whole-cell patch-clamp recording configuration in voltage-clamp mode. The antiepileptic drug phenytoin decreased glutamatergic eEPSCs in a concentration-dependent fashion by inhibiting voltage-dependent Na? and Ca˛? channel currents. In contrast, LEV had no effect on eEPSCs or voltage-dependent Na? or Ca˛? channel currents. Activation of presynaptic GABA type A (GABA(A)) receptors by muscimol induced presynaptic inhibition of eEPSCs, resulting from depolarization block. Low concentrations of Zn˛?, which had no effect on eEPSCs, voltage-dependent Na? or Ca˛? channel currents, or glutamate receptor-mediated whole cell currents, reduced the muscimol-induced presynaptic inhibition. LEV applied in the continuous presence of 1 µM muscimol and 1 µM Zn˛? reversed this Zn˛? modulation on eEPSCs. The antagonizing effect of LEV on Zn˛?-induced presynaptic GABA(A) receptor inhibition was also observed with the Zn˛? chelators Ca-EDTA and RhodZin-3. Our results clearly show that LEV removes the Zn˛?-induced suppression of GABA(A)-mediated presynaptic inhibition, resulting in a presynaptic decrease in glutamate-mediated excitatory transmission. Our results provide a novel mechanism by which LEV may inhibit neuronal activity. PMID:24259680
Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei
Pugh, Jason R.; Raman, Indira M.
Many cerebellar neurons fire spontaneously, generating 10–100 action potentials per second even without synaptic input. This high basal activity correlates with information-coding mechanisms that differ from those of cells that are quiescent until excited synaptically. For example, in the deep cerebellar nuclei, Hebbian patterns of coincident synaptic excitation and postsynaptic firing fail to induce long-term increases in the strength of excitatory inputs. Instead, excitatory synaptic currents are potentiated by combinations of inhibition and excitation that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks. Such results indicate that circuits with intrinsically active neurons have rules for information transfer and storage that distinguish them from other brain regions. PMID:19178955
Endocannabinoids in synaptic plasticity and neuroprotection.
Xu, Jian-Yi; Chen, Chu
Endocannabinoids (eCBs) are endogenous lipid mediators involved in a variety of physiological, pharmacological, and pathological processes. While activation of the eCB system primarily induces inhibitory effects on both GABAergic and glutamatergic synaptic transmission and plasticity through acting on presynaptically expressed CB1 receptors in the brain, accumulated information suggests that eCB signaling is also capable of facilitating or potentiating excitatory synaptic transmission in the hippocampus. Recent studies show that a long-lasting potentiation of excitatory synaptic transmission at Schaffer collateral (SC)-CA1 synapses is induced by spatiotemporally primed inputs, accompanying with a long-term depression of inhibitory synaptic transmission (I-LTD) in hippocampal CA1 pyramidal neurons. This input timing-dependent long-lasting synaptic potentiation at SC-CA1 synapses is mediated by 2-arachidonoylglycerol (2-AG) signaling triggered by activation of postsynaptic N-methyl-D-aspartate receptors, group I metabotropic glutamate receptors (mGluRs), and a concurrent rise in intracellular Ca(2+). Emerging evidence now also indicates that 2-AG is an important signaling mediator keeping brain homeostasis by exerting its anti-inflammatory and neuroprotective effects in response to harmful insults through CB1/2 receptor-dependent and/or -independent mechanisms. Activation of the nuclear receptor protein peroxisome proliferator-activated receptor-? apparently is one of the important mechanisms in resolving neuroinflammation and protecting neurons produced by 2-AG signaling. Thus, the information summarized in this review suggests that the role of eCB signaling in maintaining integrity of brain function is greater than what we thought previously. PMID:24571856
Synaptic plasticity and signaling in Rett syndrome.
Della Sala, Grazia; Pizzorusso, Tommaso
Rett syndrome (RTT) is a disorder that is caused in the majority of cases by mutations in the gene methyl-CpG-binding protein-2 (MeCP2). Children with RTT are generally characterized by normal development up to the first year and a half of age, after which they undergo a rapid regression marked by a deceleration of head growth, the onset of stereotyped hand movements, irregular breathing, and seizures. Animal models of RTT with good construct and face validity are available. Their analysis showed that homeostatic regulation of MeCP2 gene is necessary for normal CNS functioning and that multiple complex pathways involving different neuronal and glial cell types are disrupted in RTT models. However, it is increasingly clear that RTT pathogenetic mechanisms converge at synaptic level impairing synaptic transmission and plasticity. We review novel findings showing how specific synaptic mechanisms and related signaling pathways are affected in RTT models. PMID:23908158
Caudal ventrolateral medulla mediates baroreceptor afferent inputs to subfornical organ angiotensin II responsive neurons.
Ciriello, John
Although anatomical data indicates that the caudal ventrolateral medulla (CVLM) projects directly to the subfornical organ (SFO), little is known about the afferent information relayed through the CVLM to SFO. Experiments were done in the anesthetized rat to investigate whether CVLM neurons mediate baroreceptor afferent information to SFO and whether this afferent information alters the response of SFO neurons to systemic injections of angiotensin II (ANG II). Extracellular single unit recordings were made from 78 spontaneously discharging single units in SFO. Of these, 32 (41%) responded to microinjection of L-glutamate (L-Glu; 0.25M; 10nl) into CVLM (27/32 were inhibited and 5/32 were excited). All 32 units also were excited by systemic injections of ANG II (250ng/0.1ml, ia). However, only those units inhibited by CVLM (n=27) were found to be inhibited by the reflex activation of baroreceptors following systemic injections of phenylephrine (2?g/kg, iv). Activation of CVLM or arterial baroreceptors in conjunction with ANG II resulted in an attenuation of the SFO unit's response to ANG II. Finally, microinjections (100nl) of the synaptic blocker CoCl(2) or the non-specific glutamate receptor antagonist kynurenic acid into CVLM attenuated (10/13 units tested) the SFO neuron's response to activation of baroreceptors, but not the unit's response evoked by systemic ANG II. Taken together, these data suggest that baroreceptor afferent information relayed through CVLM functions to modulate of the activity of neurons within SFO to extracellular signals of body fluid balance. PMID:23142269
Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment
Vizi, ES; Fekete, A; Karoly, R; Mike, A
Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic–extrasynaptic receptor trafficking, neuron–glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them. PMID:20136842
Afferent discharges from venous pressoreceptors in liver
Increasing the perfusion pressure of the portal vein in isolated liver preparation in the guinea pig caused an increase in afferent discharge rate. Discharge patterns were compatible with those of the slowly adapting type. Increasing the portal venous pressure by means of intravenous injection of Locke's solution into the left jugular vein in the rabbit in vivo caused an increase
Afferent Limb of the Myotatic Reflex Arc
A. K. McIntyre
WITHIN the past decade, the use of electronic methods has laid bare much of the mechanism underlying the myotatic, or stretch, reflex of mammalian striated muscle. Outstanding among these advances are Lloyd's demonstration of the monosynaptic nature of the myotatic reflex pathway, and his disclosure that fibres of large diameter (Group I fibres) constitute the afferent limb of this reflex
Afferents to the Ventrolateral Preoptic Nucleus
Thomas C. Chou; Alvhild A. Bjorkum; Stephanie E. Gaus; Jun Lu; Thomas E. Scammell; Clifford B. Saper
Sleep is influenced by diverse factors such as circadian time, affective states, ambient temperature, pain, etc., but pathways mediating these influences are unknown. To identify pathways that may influence sleep, we examined afferents to the ventro- lateral preoptic nucleus (VLPO), an area critically implicated in promoting sleep. Injections of the retrograde tracer cholera toxin B subunit (CTB) into the VLPO
Coupling of energy metabolism and synaptic transmission at the transcriptional level: Role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and NMDA glutamate receptor subunit genes
Dhar, Shilpa S.; Wong-Riley, Margaret T. T.
Neuronal activity and energy metabolism are tightly coupled processes. Regions high in neuronal activity, especially of the glutamatergic type, have high levels of cytochrome c oxidase (COX). Perturbations in neuronal activity affect the expressions of COX and glutamatergic N-methyl-D-aspartate receptor subunit 1 (NR1). The present study sought to test our hypothesis that the coupling extends to the transcriptional level, whereby NR1 and possibly other NR subunits and COX are co-regulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), which regulates all COX subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutations, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Grin 1 (NR1), Grin 2b (NR2b) and COX subunit genes, but not of Grin2a and Grin3a genes. These transcripts were up-regulated by KCl and down-regulated by TTX in cultured primary neurons. However, silencing of NRF-1 with small interference RNA blocked the up-regulation of Grin1, Grin2b, and COX induced by KCl, and over-expression of NRF-1 rescued these transcripts that were suppressed by TTX. NRF-1 binding sites on Grin1 and Grin2b genes are also highly conserved among mice, rats, and humans. Thus, NRF-1 is an essential transcription factor critical in the co-regulation of NR1, NR2b, and COX, and coupling exists at the transcriptional level to ensure coordinated expressions of proteins important for synaptic transmission and energy metabolism. PMID:19144849
Co-Application of Corticosterone and Growth Hormone Upregulates NR2B Protein and Increases the NR2B:NR2A Ratio and Synaptic Transmission in the Hippocampus
Mahmoud, Ghada S.; Amer, Ayman S.
Objectives: This in vitro study aimed to investigate the possible mechanism underlying the protective effect of growth hormone (GH) on hippocampal function during periods of heightened glucocorticoid exposure. Methods: This study was conducted between January and June 2005 at the Joan C. Edwards School of Medicine, Marshall University, in Huntington, West Virginia, USA. The effects of the co-application of GH and corticosterone (CORT) were tested at different concentrations on the field excitatory postsynaptic potentials (fEPSPs) of the hippocampal slices of rats in two different age groups. Changes in the protein expression of N-methyl-D-aspartate receptor (NMDAR) subunits NR1, NR2B and NR2A were measured in hippocampal brain slices treated with either artificial cerebrospinal fluid (ACSF), low doses of CORT alone or both CORT and GH for three hours. Results: The co-application of CORT and GH was found to have an additive effect on hippocampal synaptic transmission compared to either drug alone. Furthermore, the combined use of low concentrations of GH and CORT was found to have significantly higher effects on the enhancement of fEPSPs in older rats compared to young ones. Both GH and CORT enhanced the protein expression of the NR2A subunit. Simultaneous exposure to low concentrations of GH and CORT significantly enhanced NR2B expression and increased the NR2B:NR2A ratio. In contrast, perfusion with CORT alone caused significant suppression in the NR1 and NR2B protein expression and a decrease in the NR2B:NR2A ratio. Conclusion: These results suggest that NMDARs provide a potential target for mediating the GH potential protective effect against stress and age-related memory and cognitive impairment. PMID:25364551
Maturation of synaptic partners: functional phenotype and synaptic organization tuned in synchrony
Hoffpauir, Brian K; Kolson, Douglas R; Mathers, Peter H; Spirou, George A
Maturation of principal neurons of the medial nucleus of the trapezoid body (MNTB) was assessed in the context of the developmental organization and activity of their presynaptic afferents, which grow rapidly to form calyces of Held and to establish mono-innervation between postnatal days (P)2 and 4. MNTB neurons and their inputs were studied from embryonic day (E)17, when the nucleus was first discernable, until P14 after the onset of hearing. Using a novel slice preparation containing portions of the cochlea, cochlear nucleus and MNTB, we determined that synaptic inputs form onto MNTB neurons at E17 and stimulation of the cochlear nucleus can evoke action potentials (APs) and Ca2+ signals. We analysed converging inputs onto individual MNTB neurons and found that competition among inputs was resolved quickly, as a single large input, typically larger than 4 nA, emerged from P3–P4. During calyx growth but before hearing onset, MNTB cells acquired their mature, phasic firing property and quantitative real-time PCR confirmed a coincident increase in low threshold K+ channel mRNA. These events occurred in concert with an increase in somatic surface area and a 7-fold increase in the current threshold (30 to >200 pA) required to evoke action potentials, as input resistance (Rin) settled from embryonic values greater than 1 G? to approximately 200 M?. We postulate that the postsynaptic transition from hyperexcitability to decreased excitability during calyx growth could provide a mechanism to establish the mature 1:1 innervation by selecting the winning calyceal input based on synaptic strength. By comparing biophysical maturation of the postsynaptic cell to alterations in presynaptic organization, we propose that maturation of synaptic partners is coordinated by synaptic activity in a process that is likely to generalize to other neural systems. PMID:20855433
Engrailed Alters the Specificity of Synaptic Connections of Drosophila Auditory Neurons with the Giant Fiber
Pézier, Adeline; Jezzini, Sami H.; Marie, Bruno
We show that a subset of sound-detecting Johnston's Organ neurons (JONs) in Drosophila melanogaster, which express the transcription factors Engrailed (En) and Invected (Inv), form mixed electrical and chemical synaptic inputs onto the giant fiber (GF) dendrite. These synaptic connections are detected by trans-synaptic Neurobiotin (NB) transfer and by colocalization of Bruchpilot-short puncta. We then show that misexpressing En postmitotically in a second subset of sound-responsive JONs causes them to form ectopic electrical and chemical synapses with the GF, in turn causing that postsynaptic neuron to redistribute its dendritic branches into the vicinity of these afferents. We also introduce a simple electrophysiological recording paradigm for quantifying the presynaptic and postsynaptic electrical activity at this synapse, by measuring the extracellular sound-evoked potentials (SEPs) from the antennal nerve while monitoring the likelihood of the GF firing an action potential in response to simultaneous subthreshold sound and voltage stimuli. Ectopic presynaptic expression of En strengthens the synaptic connection, consistent with there being more synaptic contacts formed. Finally, RNAi-mediated knockdown of En and Inv in postmitotic neurons reduces SEP amplitude but also reduces synaptic strength at the JON–GF synapse. Overall, these results suggest that En and Inv in JONs regulate both neuronal excitability and synaptic connectivity. PMID:25164665
The early causal influence of cell size upon synaptic number: the mutant gigas of Drosophila.
Meinertzhagen, I A
The number of synaptic contacts formed by a neuron is known to vary with its surface area. This could be because large neurons are able to establish more synaptic sites, or because those neurons that are able to establish more sites are subsequently able to enlarge. To test between these two possibilities clones of enlarged ommatidia were generated in the retina of the Drosophila mutant gigas, by mitotic recombination following gamma-irradiation in the third-instar larva. The numbers of afferent synaptic contacts formed by the photoreceptor terminals in the first optic neuropil, or lamina, were then counted in the adult. The terminals of mutant photoreceptors were also enlarged, but by varying degrees. The sizes of their profiles in single sections merged with the size distribution of terminals having a wild-type phenotype, lying outside the clone in the same lamina. A perimeter of 6.0 microns for the profiles of receptor terminal in cross section was established as a criterion for distinguishing between normal and mutant phenotypes. The mutant terminals had more presynaptic sites. Because only the gigas terminals are mutant and because they enlarged at a time long before synapse formation occurred in the lamina we may conclude that cell enlargement preceded elevated synaptic number. The increase in synaptic number roughly matched the increased membrane surface of the terminals, so as nearly to preserve a constant areal density of synaptic sites over a 5-fold range in synaptic frequency. PMID:7965385
Afferent baroreflex failure in familial dysautonomia
Norcliffe-Kaufmann, Lucy; Axelrod, Felicia; Kaufmann, Horacio
Background: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause. Methods: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons. Results: During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF. Conclusion: The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients. GLOSSARY FD = familial dysautonomia; FVR = forearm vascular resistance; PAF = pure autonomic failure. PMID:21098405
Human visceral afferent recordings: preliminary report
Madusha Peiris; David C Bulmer; Mark D Baker; George Boundouki; Sidhartha Sinha; Anthony Hobson; Kevin Lee; Qasim Aziz; Charles H Knowles
BackgroundConditions characterised by chronic visceral pain represent a significant healthcare burden with limited treatment options. While animal models have provided insights into potential mechanisms of visceral nociception and identified candidate drug targets, these have not translated into successful treatments in humans.ObjectiveTo develop an in vitro afferent nerve preparation using surgically excised freshly isolated human colon and vermiform appendix-mesentery tissues.MethodsNon-inflamed appendix
Inhibitory control at a synaptic relay.
Awatramani, Gautam B; Turecek, Rostislav; Trussell, Laurence O
The mammalian medial nucleus of the trapezoid body (MNTB) harbors one of the most powerful terminals in the CNS, the calyx of Held. The mechanisms known to regulate this synaptic relay are relatively ineffective. Here, we report the presence of a remarkably robust and fast-acting glycinergic inhibitory system capable of suppressing calyceal transmission. Evoked glycinergic IPSCs were relatively small in 2-week-old rats, an age by which calyceal maturation has reportedly neared completion. However, by postnatal day 25 (P25), glycinergic transmission had undergone a vigorous transformation, resulting in peak synaptic conductances as high as 280 nS. These are comparable with glutamatergic conductances activated by calyceal inputs. Decay kinetics for IPSCs were severalfold faster than for glycinergic synaptic events reported previously. At physiological temperatures in P25 rats, IPSCs decayed in approximately 1 msec and could be elicited at frequencies up to 500 Hz. Moreover, EPSPs triggered by glutamatergic signals derived from the calyx or simulated by conductance clamp were suppressed when preceded by simulated glycinergic IPSPs. The matching of excitatory transmission in the calyx of Held by a powerful, precision inhibitory system suggests that the relay function of the MNTB may be rapidly modified during sound localization. PMID:15028756
Drosophila melanogaster Scramblases modulate synaptic transmission
Acharya, Usha; Edwards, Michael Beth; Jorquera, Ramon A.; Silva, Hugo; Nagashima, Kunio; Labarca, Pedro; Acharya, Jairaj K.
Scramblases are a family of single-pass plasma membrane proteins, identified by their purported ability to scramble phospholipids across the two layers of plasma membrane isolated from platelets and red blood cells. However, their true in vivo role has yet to be elucidated. We report the generation and isolation of null mutants of two Scramblases identified in Drosophila melanogaster. We demonstrate that flies lacking either or both of these Scramblases are not compromised in vivo in processes requiring scrambling of phospholipids. Instead, we show that D. melanogaster lacking both Scramblases have more vesicles and display enhanced recruitment from a reserve pool of vesicles and increased neurotransmitter secretion at the larval neuromuscular synapses. These defects are corrected by the introduction of a genomic copy of the Scramb 1 gene. The lack of phenotypes related to failure of scrambling and the neurophysiological analysis lead us to propose that Scramblases play a modulatory role in the process of neurotransmission. PMID:16606691
Evolutionarily conserved differences in pallial and thalamic short-term synaptic plasticity in striatum
Ericsson, Jesper; Stephenson-Jones, Marcus; Kardamakis, Andreas; Robertson, Brita; Silberberg, Gilad; Grillner, Sten
The striatum of the basal ganglia is conserved throughout the vertebrate phylum. Tracing studies in lamprey have shown that its afferent inputs are organized in a manner similar to that of mammals. The main inputs arise from the thalamus (Th) and lateral pallium (LPal; the homologue of cortex) that represents the two principal excitatory glutamatergic inputs in mammals. The aim here was to characterize the pharmacology and synaptic dynamics of afferent fibres from the LPal and Th onto identified striatal neurons to understand the processing taking place in the lamprey striatum. We used whole-cell current-clamp recordings in acute slices of striatum with preserved fibres from the Th and LPal, as well as tract tracing and immunohistochemistry. We show that the Th and LPal produce monosynaptic excitatory glutamatergic input through NMDA and AMPA receptors. The synaptic input from the LPal displayed short-term facilitation, unlike the Th input that instead displayed strong short-term synaptic depression. There was also an activity-dependent recruitment of intrastriatal oligosynaptic inhibition from both inputs. These results indicate that the two principal inputs undergo different activity-dependent short-term synaptic plasticity in the lamprey striatum. The difference observed between Th and LPal (cortical) input is also observed in mammals, suggesting a conserved trait throughout vertebrate evolution. PMID:23148315
Afferent innervation patterns of the saccule in pigeons.
Zakir, M; Huss, D; Dickman, J D
The innervation patterns of vestibular saccular afferents were quantitatively investigated in pigeons using biotinylated dextran amine as a neural tracer and three-dimensional computer reconstruction. Type I hair cells were found throughout a large portion of the macula, with the highest density observed in the striola. Type II hair cells were located throughout the macula, with the highest density in the extrastriola. Three classes of afferent innervation patterns were observed, including calyx, dimorph, and bouton units, with 137 afferents being anatomically reconstructed and used for quantitative comparisons. Calyx afferents were located primarily in the striola, innervated a number of type I hair cells, and had small innervation areas. Most calyx afferent terminal fields were oriented parallel to the anterior-posterior axis and the morphological polarization reversal line. Dimorph afferents were located throughout the macula, contained fewer type I hair cells in a calyceal terminal than calyx afferents and had medium sized innervation areas. Bouton afferents were restricted to the extrastriola, with multi-branching fibers and large innervation areas. Most of the dimorph and bouton afferents had innervation fields that were oriented dorso-ventrally but were parallel to the neighboring reversal line. The organizational morphology of the saccule was found to be distinctly different from that of the avian utricle or lagena otolith organs and appears to represent a receptor organ undergoing evolutionary adaptation toward sensing linear motion in terrestrial and aerial species. PMID:12522200
Sleep and synaptic homeostasis.
Vyazovskiy, Vladyslav V; Faraguna, Ugo
In the last decades a substantial knowledge about sleep mechanisms has been accumulated. However, the function of sleep still remains elusive. The difficulty with unraveling sleep's function may arise from the lack of understanding of how the multitude of processes associated with waking and sleep-from gene expression and single neuron activity to the whole brain dynamics and behavior-functionally and mechanistically relate to each other. Therefore, novel conceptual frameworks, which integrate and take into account the variety of phenomena occurring during waking and sleep at different levels, will likely lead to advances in our understanding of the function of sleep, above and beyond what merely descriptive or correlative approaches can provide. One such framework, the synaptic homeostasis hypothesis, focuses on wake- and sleep-dependent changes in synaptic strength. The core claim of this hypothesis is that learning and experience during wakefulness are associated with a net increase in synaptic strength. In turn, the proposed function of sleep is to provide synaptic renormalization, which has important implications with respect to energy needs, intracranial space, metabolic supplies, and, importantly, enables further plastic changes. In this article we review the empirical evidence for this hypothesis, which was obtained at several levels-from gene expression and cellular excitability to structural synaptic modifications and behavioral outcomes. We conclude that although the mechanisms behind the proposed role of sleep in synaptic homeostasis are undoubtedly complex, this conceptual framework offers a unique opportunity to provide mechanistic and functional explanation for many previously disparate observations, and define future research strategies. PMID:24844680
Botulinum toxin B in the sensory afferent: transmitter release, spinal activation, and pain behavior.
Marino, Marc J; Terashima, Tetsuji; Steinauer, Joanne J; Eddinger, Kelly A; Yaksh, Tony L; Xu, Qinghao
We addressed the hypothesis that intraplantar botulinum toxin B (rimabotulinumtoxin B: BoNT-B) has an early local effect upon peripheral afferent terminal releasing function and, over time, will be transported to the central terminals of the primary afferent. Once in the terminals it will cleave synaptic protein, block spinal afferent transmitter release, and thereby prevent spinal nociceptive excitation and behavior. In mice, C57Bl/6 males, intraplantar BoNT-B (1 U) given unilaterally into the hind paw had no effect upon survival or motor function, but ipsilaterally decreased: (1) intraplantar formalin-evoked flinching; (2) intraplantar capsaicin-evoked plasma extravasation in the hind paw measured by Evans blue in the paw; (3) intraplantar formalin-evoked dorsal horn substance P (SP) release (neurokinin 1 [NK1] receptor internalization); (4) intraplantar formalin-evoked dorsal horn neuronal activation (c-fos); (5) ipsilateral dorsal root ganglion (DRG) vesicle-associated membrane protein (VAMP); (6) ipsilateral SP release otherwise evoked bilaterally by intrathecal capsaicin; (7) ipsilateral activation of c-fos otherwise evoked bilaterally by intrathecal SP. These results indicate that BoNT-B, after unilateral intraplantar delivery, is taken up by the peripheral terminal, is locally active (blocking plasma extravasation), is transported to the ipsilateral DRG to cleave VAMP, and is acting presynaptically to block release from the spinal peptidergic terminal. The observations following intrathecal SP offer evidence for a possible transsynaptic effect of intraplantar BoNT. These results provide robust evidence that peripheral BoNT-B can alter peripheral and central terminal release from a nociceptor and attenuate downstream nociceptive processing via a presynaptic effect, with further evidence suggesting a possible postsynaptic effect. PMID:24333775
Synaptic hyperpolarization and inhibition of turtle cochlear hair cells.
Art, J J; Fettiplace, R; Fuchs, P A
Intracellular recordings were made from turtle cochlear hair cells in order to examine the properties of the post-synaptic potentials evoked by electrical stimulation of the efferent axons. Single shocks to the efferents generated a hair cell membrane hyperpolarization with an average amplitude generally less than 1 mV and lasting for about 100 ms. With short trains of shocks, the size of the post-synaptic potential grew markedly to a maximum of 20-30 mV. The interaction between pairs of shocks separated by a varying interval was studied. For an interval of 4 ms, the response to the second shock was increased on average by a factor of 3 and the conditioning effect of the first shock decayed with a time constant of about 100 ms. We suggest the augmentation in response to trains of shocks may be partly due to facilitation of efferent transmitter release. The efferent post-synaptic potentials could be reversibly abolished by perfusion with perilymphs containing 3 microM-curare or atropine, and infusion of acetylcholine gave a transient membrane hyperpolarization. These observations are consistent with efferent action being mediated via a cholinergic synapse onto the hair cells. The post-synaptic potentials could be reversed in polarity by injection of hyperpolarizing currents through the recording electrode. The reversal potential was estimated as about -80 mV, 30 mV negative to the resting potential. Near reversal, a small brief depolarization was evident and may constitute a minor component of the synaptic response. The value of the reversal potential was unaffected by substitution of the perilymphatic chloride, but was altered in a predictable manner by changes in extracellular potassium concentration indicating that the post-synaptic potentials arise mainly by an increase in the permeability of the hair cell membrane to potassium ions. Throughout the post-synaptic hyperpolarization there was a reduction in the sensitivity of the hair cell to tones at its characteristic frequency. The desensitization, maximal for low sound pressures, varied in different cells from a factor of 1.6 to 28. At the peak of the largest synaptic potentials, the receptor potential remained negative to the resting potential with all but the loudest characteristic frequency tone s. We suggest that there are two factors in efferent inhibition; one a r duction in the receptor potential at the hair cell's characteristic frequency and the other a hyperpolarization of its membrane potential which should reduce the release of excitatory transmitter onto the afferent terminals. Images Fig. 9 PMID:6097676
The Edinger-Westphal nucleus II: Hypothalamic afferents in the rat.
da Silva, André V; Torres, Kelly R; Haemmerle, Carlos A; Céspedes, Isabel C; Bittencourt, Jackson C
Numerous functions have been attributed to the Edinger-Westphal nucleus (EW), including those related to feeding behavior, pain control, alcohol consumption and the stress response. The EW is thought to consist of two parts: one controls accommodation, choroidal blood flow and pupillary constriction, primarily comprising cholinergic cells and projecting to the ciliary ganglion; and the other would be involved in the non-ocular functions mentioned above, comprising peptide-producing neurons and projecting to the brainstem, spinal cord and prosencephalic regions. Despite the fact that the EW is well known, its connections have yet to be described in detail. The aim of this work was to produce a map of the hypothalamic sources of afferents to the EW in the rat. We injected the retrograde tracer Fluoro-Gold into the EW, and using biotinylated dextran amine, injected into afferent sources as the anterograde control. We found retrogradely labeled cells in the following regions: subfornical organ, paraventricular hypothalamic nucleus, arcuate nucleus, lateral hypothalamic area, zona incerta, posterior hypothalamic nucleus, medial vestibular nucleus and cerebellar interpositus nucleus. After injecting BDA into the paraventricular hypothalamic nucleus, lateral hypothalamic area and posterior hypothalamic nucleus, we found anterogradely labeled fibers in close apposition to and potential synaptic contact with urocortin 1-immunoreactive cells in the EW. On the basis of our findings, we can suggest that the connections between the EW and the hypothalamic nuclei are involved in controlling stress responses and feeding behavior. PMID:23619059
Experimental degeneration of primary afferent terminals in the cuneate nucleus of the monkey (Macaca fascicularis).
Wen, C Y; Tan, C K; Wong, W C
Six monkeys (Macaca fascicularis) were used for the present study. In animals which survived for 2-6 days after section of C5 to T1 dorsal roots, at least four types of degenerating afferent terminal were observed - electron-dense, electron-lucent, neurofilamentous and flocculent. The electron-dense degeneration was the most common and was seen as early as 2 days after rhizotomy. The neurofilamentous type was the second commonest and was found predominantly in the 3 days' survival material. The electron-lucent and flocculent types were less commonly encountered. Since the profiles exhibiting neurofilamentous hyperplasia showed varying degrees of electron density it is suggested that this type of degeneration progresses to the electron-dense type with time. The present study also showed that the primary afferent terminals in the cuneate nucleus of the monkey are mostly large and that they contain round vesicles. They are commonly found within synaptic complexes in which they are presynaptic to dendrites of various sizes, and are themselves postsynaptic to smaller axon terminals containing flattened vesicles. Degenerating terminals forming isolated synapses were less commonly seen. No dorsal root axon terminals formed axosomatic synapses. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 PMID:114509
Ontogeny of synaptophysin and synaptoporin in the central nervous system: differential expression in striatal neurons and their afferents during development.
Ovtscharoff, W; Bergmann, M; Marqučze-Pouey, B; Knaus, P; Betz, H; Grabs, D; Reisert, I; Gratzl, M
The expression of the synaptic vesicle antigens synaptophysin (SY) and synaptoporin (SO) was studied in the rat striatum, which contains a nearly homogeneous population of GABAergic neurons. In situ hybridization revealed high levels of SY transcripts in the striatal anlage from embryonic day (E) 14 until birth. In contrast, SO hydridization signals were low, and no immunoreactive cell bodies were detected at these stages of development. At E 14, SY-immunoreactivity was restricted to perikarya. In later prenatal stages of development SY-immunoreactivity appeared in puncta (identified as terminals containing immunostained synaptic vesicles), fibers, thick fiber bundles and 'patches'. In postnatal and adult animals, perikarya of striatal neurons exhibited immunoreaction for SO; ultrastructurally SO antigen was found in the Golgi apparatus and in multivesicular bodies. SO-positive boutons were rare in the striatum. In the neuropil, numerous presynaptic terminals positive for SY were observed. Our data indicate that the expression of synaptic vesicle proteins in GABAergic neurons of the striatum is developmentally regulated. Whereas SY is prevalent during embryonic development, SO is the major synaptic vesicle antigen expressed postnatally by striatal neurons which project to the globus pallidus and the substantia nigra. In contrast synapses of striatal afferents (predominantly from cortex, thalamus and substantia nigra) contain SY. PMID:8485845
Neural variability, detection thresholds, and information transmission in the vestibular system.
Sadeghi, Soroush G; Chacron, Maurice J; Taylor, Michael C; Cullen, Kathleen E
A fundamental issue in neural coding is the role of spike timing variation in information transmission of sensory stimuli. Vestibular afferents are particularly well suited to study this issue because they are classified as either regular or irregular based on resting discharge variability as well as morphology. Here, we compared the responses of each afferent class to sinusoidal and random head rotations using both information theoretic and gain measures. Information theoretic measures demonstrated that regular afferents transmitted, on average, two times more information than irregular afferents, despite having significantly lower gains. Moreover, consistent with information theoretic measures, regular afferents had angular velocity detection thresholds that were 50% lower than those of irregular afferents (approximately 4 vs 8 degrees/s). Finally, to quantify the information carried by spike times, we added spike-timing jitter to the spike trains of both regular and irregular afferents. Our results showed that this significantly reduced information transmitted by regular afferents whereas it had little effect on irregular afferents. Thus, information is carried in the spike times of regular but not irregular afferents. Using a simple leaky integrate and fire model with a dynamic threshold, we show that differential levels of intrinsic noise can explain differences in the resting discharge, the responses to sensory stimuli, as well as the information carried by action potential timings of each afferent class. Our experimental and modeling results provide new insights as to how neural variability influences the strategy used by two different classes of sensory neurons to encode behaviorally relevant stimuli. PMID:17251416
Lipid signaling: sleep, synaptic plasticity, and neuroprotection.
Chen, Chu; Bazan, Nicolas G
Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367:175; Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance. Proc Natl Acad Sci USA 1995; 92:5047; Chen C, Magee CJ, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 2002; 87:2851]. Recently, we found that prolonged continuous wakefulness (primarily rapid eye movement (REM)-sleep deprivation, SD) causes impairments in hippocampal long-term synaptic plasticity and hippocampus-dependent memory formation [McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci 2003; 23:9687]. To explore the mechanisms underlying SD-induced impairments, we have studied several bioactive lipids in the hippocampus following SD. It appears that SD causes increases in prostaglandin D2 (PGD2) and 2-arachidonylglycerol (2-AG), and a decrease in PGE2, suggesting that these lipid messengers participate in memory consolidation during REM sleep. We have also explored the formation of endogenous neuroprotective lipids. Toward this aim, we have used ischemia-reperfusion damage and LC-PDA-ESI-MS-MS-based lipidomic analysis and identified docosanoids derived from synaptic phospholipid-enriched docosahexaenoic acid. Some of the docosanoids exert potent neuroprotective bioactivity [Marcheselli VL, Hong S, Lukiw WJ, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003; 278:43807; Mukherjee PK, Marcheselli VL, Serhan CN, Bazan, NG. Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Nat Acad Sci USA 2004; 101:8491). Taken together, these observations that signaling lipids participate in synaptic plasticity, cognition, and survival indicate that lipid signaling is closely associated with several functions (e.g; learning and memory, sleep, and experimental stroke) and pathologic events. Alterations in endogenous signaling lipids or their receptors resulting from drug abuse lead to changes in synaptic circuitry and induce profound effects on these important functions. In the present article, we will briefly review bioactive lipids involved in sleep, synaptic transmission and plasticity, and neuroprotection, focusing mainly on our experimental studies and how these signaling molecules are related to functions and implicated in some neurologic disorders. PMID:16099392
Asymmetric Synaptic Depression in
Mircea I. Chelaru; Valentin Dragoi
Synaptic depression is essential for controlling the balance be- tween excitation and inhibition in cortical networks. Several studies have shown that the depression of intracortical synapses is asymmetric, that is, inhibitory synapses depress less than excit- atory ones. Whether this asymmetry has any impact on cortical function is unknown. Here we show that the differential depression of intracortical synapses provides
Synaptic plasticity: hippocampal LTP
Alan U Larkman; J Julian B Jack
One of the most intensively studied forms of synaptic plasticity is long-term potentiation (LTP). The past year has seen further evidence advanced on both sides of the presynaptic\\/postsynaptic locus of expression debate, without an obvious path to reconcile the two views. Real progress has been made, however, in clarifying the possible role of nitric oxide as a retrograde messenger and
Synaptic plasticity and addiction
Julie A. Kauer; Robert C. Malenka
Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the
Actions of excitatory amino acid antagonists on synaptic inputs to the rat medial vestibular nucleus: an electrophysiological study in vitro
K. Doi; T. Tsumoto; T. Matsunaga
The actions of excitatory amino acid (EAA) antagonists on synaptic inputs to neurons in the rat medial vestibular nucleus (MVN) from ipsilateral vestibular afferents and vestibular commissures were studied in brain stem slice preparations. Antagonists used were 2-amino-5-phosphonovalerate (APV), a selective antagonist for the N-methyl-D-aspartate (NMDA) type of EAA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective antagonist for the quisqualate\\/kainate (non-NMDA) type
Synaptic reorganization of calbindin-positive neurons in the human hippocampal CA1 region in temporal lobe epilepsy
L. WITTNER; L. EROSS; Z. SZABO; Sz Tóth; S Czirják; P Halász; T. F Freund; Zs Maglóczky
The distribution, morphology, synaptic coverage and postsynaptic targets of calbindin-containing interneurons and afferent pathways have been analyzed in the control and epileptic CA1 region of the human hippocampus. Numerous calbindin-positive interneurons are preserved even in the strongly sclerotic CA1 region. The morphology of individual cells is altered: the cell body and dendrites become spiny, the radially oriented dendrites disappear, and
We used horseradish peroxidase (HRP) to orthogradely label afferent axons in macaque striate cortex. Of the 38 axons that we recovered, nine were recorded intracelhrlarly before being filled with HRP. Light microscope and computer reconstructions of filled processes reveal highly stereotyped patterns of arborization and suggest that there are at least five discrete populations of lateral geniculate nucleus (LGN) afferent
Muscle weakness, afferent sensory dysfunction and exercise in knee osteoarthritis
Walter Herzog; Joel A. Block; Kim L. Bennell; Ewa M. Roos
Lower-extremity muscle strength and afferent sensory dysfunction, such as reduced proprioceptive acuity, are potentially modifiable putative risk factors for knee osteoarthritis (OA). Findings from current studies suggest that muscle weakness is a predictor of knee OA onset, while there is conflicting evidence regarding the role of muscle weakness in OA progression. In contrast, the literature suggests a role for afferent
Response properties from turtle auditory hair cell afferent fibers suggest spike generation is driven by synchronized release both between and within synapses
Schnee, M. E.; Castellano-Muńoz, M.
Inner ear hair cell afferent fiber synapses are capable of transferring information at high rates for long periods of time with extraordinary fidelity. As at other sensory synapses, hair cells rely on graded receptor potentials and unique vesicle trafficking and release properties of ribbon synapses to relay intensity information. Postsynaptic recordings from afferent fibers of the turtle auditory papilla identified excitatory postsynaptic currents (EPSCs) that were fast AMPA receptor-based responses with rapid onset and decay times. EPSCs varied in amplitude by ?15× per fiber, with kinetics that showed a tendency to slow at larger amplitudes. Complex EPSCs were produced by temporal summation of single events, likely across synapses. Complex EPSCs were more efficient at generating action potentials than single EPSCs. Potassium-evoked release increased the frequency of EPSCs, in particular complex events, but did not increase EPSC amplitudes. Temporal summation of EPSCs across synapses may underlie action potential generation at these synapses. Broad amplitude histograms were probed for mechanisms of multivesicular release with reduced external Ca2+ or the introduction of Cd2+ or Sr2+ to uncouple release. The results are consistent with broad amplitude histograms being generated by a combination of the variability in synaptic vesicle size and coordinated release of these vesicles. It is posited that multivesicular release plays less of a role in multisynaptic ribbon synapses than in single synaptic afferent fibers. PMID:23596330
Ginger and its pungent constituents non-competitively inhibit serotonin currents on visceral afferent neurons.
Jin, Zhenhua; Lee, Goeun; Kim, Sojin; Park, Cheung-Seog; Park, Yong Seek; Jin, Young-Ho
Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons. PMID:24757377
Increased Expression of Alpha-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering After Endocytosis
Nemani, Venu M.; Lu, Wei; Berge, Victoria; Nakamura, Ken; Onoa, Bibiana; Lee, Michael K.; Chaudhry, Farrukh A.; Nicoll, Roger A.; Edwards, Robert H.
Summary The protein ?-synuclein accumulates in the brain of patients with sporadic Parkinson's disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration. ?-Synuclein localizes to the nerve terminal, but the knockout has little if any effect on synaptic transmission. In contrast, we now find that the modest over-expression of ?-synuclein, in the range predicted for gene multiplication and in the absence of overt toxicity, markedly inhibits neurotransmitter release. The mechanism, elucidated by direct imaging of the synaptic vesicle cycle, involves a specific reduction in size of the synaptic vesicle recycling pool. Ultrastructural analysis demonstrates reduced synaptic vesicle density at the active zone, and imaging further reveals a defect in the reclustering of synaptic vesicles after endocytosis. Increased levels of ?-synuclein thus produce a specific, physiological defect in synaptic vesicle recycling that precedes detectable neuropathology. PMID:20152114
NASA Astrophysics Data System (ADS)
Pisarchik, A. N.; Jaimes-Reátegui, R.; Sevilla-Escoboza, R.; García-Lopez, J. H.; Kazantsev, V. B.
Understanding neuron connections is a great challenge, which is needed to solve many important problems in neurobiology and neuroengineering for recreation of brain functions and efficient biorobotics. In particular, a design of an optical synapse capable to communicate with neuron spike sequences would be crucial to improve the functionality of neuromimmetic networks. In this work we propose an optical synaptic sensor based on an erbium-doped fiber laser driven by a FitzHung-Nagumo electronic neuron, to connect with another electronic neuron. Two possible optical synaptic configurations are analyzed for optoelectronic coupling between neurons: laser cavity loss modulation and pump laser modulation. The control parameters of the proposed optical synapse provide additional degrees of flexibility to the neuron connection traditionally controlled only by coupling strengths in artificial networks.
BDNF-induced local protein synthesis and synaptic plasticity.
Leal, Graciano; Comprido, Diogo; Duarte, Carlos B
Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-? (PLC-?) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID:23602987
Thalamic projection of muscle nerve afferents in the cat
Mallart, A.
1. Evoked responses on stimulation of hind- and forelimb muscle nerves have been recorded in the ventro-postero-lateral (VPL) and centre median (CM) nuclei of the thalamus of the cat. 2. The stimulation of hind-limb muscle afferents with increasing strength usually did not evoke a thalamic response, either in the CM or in the VPL, until the threshold for Group III muscle afferents was reached. 3. Short latency potentials were evoked in the VPL on stimulation of low threshold Group I muscle afferents from forelimbs. The projection zone occupies the dorso-medio-rostral part of the nucleus. 4. An attempt was made to locate the medullary relay for forelimb Group I afferents either in the lateral part of the cuneate or in external cuneate. 5. Low threshold afferents from forelimb muscle nerves do not project to the CM. CM responses began to appear only when the threshold for Group II muscle nerve fibres was reached. 6. Group II afferents from hind- or forelimb muscle nerves projecting to the CM are probably not connected to spindle secondary endings. 7. The role played by muscle afferents in the somesthetic mechanisms is briefly discussed. PMID:5639358
[Peptidergic modulation of the hippocampus synaptic activity].
Skrebitski?, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I
Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent. PMID:22390072
In vivo long-term synaptic plasticity of glial cells
Bélair, Eve-Lyne; Vallée, Joanne; Robitaille, Richard
Evidence showing the ability of glial cells to detect, respond to and modulate synaptic transmission and plasticity has contributed to the notion of glial cells as active synaptic partners. However, synaptically induced plasticity of glia themselves remains ill defined. Here we used the amphibian neuromuscular junction (NMJ) to study plasticity of perisynaptic Schwann cells (PSCs), glial cells at this synapse, following long-term in vivo modifications of synaptic activity. We used two models that altered synaptic activity in different manners. First, chronic blockade of postsynaptic nicotinic receptors using ?-bungarotoxin (?-BTx) decreased facilitation, increased synaptic depression and decreased post-tetanic potentiation (PTP). Second, chronic nerve stimulation increased facilitation and resistance to synaptic depression, while leaving PTP unaltered. Our results indicate that there is no direct relationship between transmitter release and PSC calcium responses. Indeed, despite changes in transmitter release and plasticity in stimulated NMJs, nerve-evoked PSC calcium responses were similar to control. Similarly, PSC calcium responses in ?-BTx treated NMJs were delayed and smaller in amplitude, even though basal level of transmitter release was increased. Also, when isolating purinergic and muscarinic components of PSC calcium responses, we found an increased sensitivity to ATP and a decreased sensitivity to muscarine in chronically stimulated NMJs. Conversely, in ?-BTx treated NMJs, PSC sensitivity remained unaffected, but ATP- and muscarine-induced calcium responses were prolonged. Thus, our results reveal complex modifications of PSC properties, with differential modulation of signalling pathways that might underlie receptor regulation or changes in Ca2+ handling. Importantly, similar to neurons, perisynaptic glial cells undergo plastic changes induced by altered synaptic activity. PMID:20142269
Tracking slow modulations in synaptic gain using dynamic causal modelling: validation in epilepsy.
Papadopoulou, Margarita; Leite, Marco; van Mierlo, Pieter; Vonck, Kristl; Lemieux, Louis; Friston, Karl; Marinazzo, Daniele
In this work we propose a proof of principle that dynamic causal modelling can identify plausible mechanisms at the synaptic level underlying brain state changes over a timescale of seconds. As a benchmark example for validation we used intracranial electroencephalographic signals in a human subject. These data were used to infer the (effective connectivity) architecture of synaptic connections among neural populations assumed to generate seizure activity. Dynamic causal modelling allowed us to quantify empirical changes in spectral activity in terms of a trajectory in parameter space - identifying key synaptic parameters or connections that cause observed signals. Using recordings from three seizures in one patient, we considered a network of two sources (within and just outside the putative ictal zone). Bayesian model selection was used to identify the intrinsic (within-source) and extrinsic (between-source) connectivity. Having established the underlying architecture, we were able to track the evolution of key connectivity parameters (e.g., inhibitory connections to superficial pyramidal cells) and test specific hypotheses about the synaptic mechanisms involved in ictogenesis. Our key finding was that intrinsic synaptic changes were sufficient to explain seizure onset, where these changes showed dissociable time courses over several seconds. Crucially, these changes spoke to an increase in the sensitivity of principal cells to intrinsic inhibitory afferents and a transient loss of excitatory-inhibitory balance. PMID:25498428
A Physiologic Role for Serotonergic Transmission in Adult Rat Taste Buds
Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott
Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the afferent signal. Serotonin may thus play a major modulatory role within peripheral taste in shaping the afferent taste signals prior to their transmission across gustatory nerves. PMID:25386961
NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale.
Delekate, Andrea; Zagrebelsky, Marta; Kramer, Stella; Schwab, Martin E; Korte, Martin
Whereas the role of NogoA in limiting axonal fiber growth and regeneration following an injury of the mammalian central nervous system (CNS) is well known, its physiological functions in the mature uninjured CNS are less well characterized. NogoA is mainly expressed by oligodendrocytes, but also by subpopulations of neurons, in particular in plastic regions of the CNS, e.g., in the hippocampus where it is found at synaptic sites. We analyzed synaptic transmission as well as long-term synaptic plasticity (long-term potentiation, LTP) in the presence of function blocking anti-NogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO mice. Whereas baseline synaptic transmission, short-term plasticity and long-term depression were not affected by either approach, long-term potentiation was significantly increased following NogoA or NgR1 neutralization. Synaptic potentiation thus seems to be restricted by NogoA. Surprisingly, synaptic weakening was not affected by interfering with NogoA signaling. Mechanistically of interest is the observation that by blockade of the GABA(A) receptors normal synaptic strengthening reoccurred in the absence of NogoA signaling. The present results show a unique role of NogoA expressed in the adult hippocampus in restricting physiological synaptic plasticity on a very fast time scale. NogoA could thus serve as an important negative regulator of functional and structural plasticity in mature neuronal networks. PMID:21262805
Differential central projections of vestibular afferents in pigeons
NASA Technical Reports Server (NTRS)
Dickman, J. D.; Fang, Q.
The question of whether a differential distribution of vestibular afferent information to central nuclear neurons is present in pigeons was studied using neural tracer compounds. Discrete tracing of afferent fibers innervating the individual semicircular canal and otolith organs was produced by sectioning individual branches of the vestibular nerve that innervate the different receptor organs and applying crystals of horseradish peroxidase, or a horseradish peroxidase/cholera toxin mixture, or a biocytin compound for neuronal uptake and transport. Afferent fibers and their terminal distributions within the brainstem and cerebellum were visualized subsequently. Discrete areas in the pigeon central nervous system that receive primary vestibular input include the superior, dorsal lateral, ventral lateral, medial, descending, and tangential vestibular nuclei; the A and B groups; the intermediate, medial, and lateral cerebellar nuclei; and the nodulus, the uvula, and the paraflocculus. Generally, the vertical canal afferents projected heavily to medial regions in the superior and descending vestibular nuclei as well as the A group. Vertical canal projections to the medial and lateral vestibular nuclei were observed but were less prominent. Horizontal canal projections to the superior and descending vestibular nuclei were much more centrally located than those of the vertical canals. A more substantial projection to the medial and lateral vestibular nuclei was seen with horizontal canal afferents compared to vertical canal fibers. Afferents innervating the utricle and saccule terminated generally in the lateral regions of all vestibular nuclei in areas that were separate from the projections of the semicircular canals. In addition, utricular fibers projected to regions in the vestibular nuclei that overlapped with the horizontal semicircular canal terminal fields, whereas saccular afferents projected to regions that received vertical canal fiber terminations. Lagenar afferents projected throughout the cochlear nuclei, to the dorsolateral regions of the cerebellar nuclei, and to lateral regions of the superior, lateral, medial, and descending vestibular nuclei.
Eugenol Inhibits Calcium Currents in Dental Afferent Neurons
M. H. Lee; K.-Y. Yeon; C.-K. Park; H.-Y. Li; Z. Fang; M. S. Kim; S.-Y. Choi; S. J. Lee; J.-H. Lee; J. S. Kim; S. B. Oh
Eugenol is a topical analgesic agent widely used in the dental clinic. To elucidate the molecular mechanism underlying its analgesic action, we investigated the effect of eugenol on high-voltage-activated calcium channel (HVACC) currents in dental primary afferent neurons, and with a heterologous expression system. Dental primary afferent neurons were identified by retrograde labeling with a fluorescent dye, DiI. Eugenol inhibited
Synaptic Plasticity and Translation Initiation
ERIC Educational Resources Information Center
Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei
It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…
Distinctive roles of different ?-amyloid 42 aggregates in modulation of synaptic functions
Chiang, Hsueh-Cheng; Iijima, Koichi; Hakker, Inessa; Zhong, Yi
To determine how endogenously secreted ?-amyloid 42 (A?42) aggregates regulate synaptic functions, we examined effects of A?42 at the neuromuscular junction of Drosophila larvae. Voltage-clamp recordings of synaptic transmission and optical analysis of vesicle recycling at presynaptic terminals show that expression of A?42 in neurons leads to a reduction of neurotransmitter release. However, expression of A?42 in postsynaptic muscle cells enhanced neurotransmitter release. Both effects are neutralized by A? antibody, suggesting a role for secreted A?42 peptides. Application of exogenously prepared A?42 oligomers leads to a reduction in synaptic responses, whereas mixed A?42 aggregates with mainly fibrils elicit an opposite effect by increasing synaptic transmission. Further analysis of long-term depression (LTD) confirms differential effects of different A?42 aggregates. Taken together, our data suggest that A?42 is secreted from neurons primarily as oligomers that inhibit neurotransmitter release and exert no effect on LTD. Whereas larger-sized aggregates, possibly fibrils, are major components secreted from muscle cells, which enhance synaptic transmission and LTD. Thus, different types of cells may secrete distinct forms of A?42 aggregates, leading to different modulation of synaptic functions.—Chiang, H.-C., Iijima, K., Hakker, I., Zhong, Y. Distinctive roles of different ?-amyloid 42 aggregates in modulation of synaptic functions. PMID:19255256
The effects of stress on glutamatergic transmission in the brain.
Yuan, Ti-Fei; Hou, Gonglin
Stress leads to detrimental effects on brain functions and results in various diseases. Recent studies highlight the involvement of glutamatergic transmission in pathogenesis of depressive behaviors and fears. Acute stress generates different impacts on the excitatory transmission compared to chronic stress. Different neuromodulators and epigenetic factors also participate in the alteration of synaptic transmission and the regulation of synaptic plasticity. Restoration of the glutamatergic transmission in stress-affected brain areas therefore provides novel directions of therapeutic interventions against stress. PMID:24939697
Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry.
Kravets, J L; Reyes, B A S; Unterwald, E M; Van Bockstaele, E J
Amygdalar norepinephrine (NE) plays a key role in regulating neural responses to emotionally arousing stimuli and is involved in memory consolidation of emotionally charged events. Corticotropin-releasing factor (CRF) and dynorphin (DYN), two neuropeptides that mediate the physiological and behavioral responses to stress, are abundant in the central nucleus of the amygdala (CeA), and directly innervate brainstem noradrenergic locus coeruleus (LC) neurons. Whether the CRF- and DYN-containing amygdalar neurons receive direct noradrenergic innervation has not yet been elucidated. The present study sought to define cellular substrates underlying noradrenergic modulation of CRF- and DYN-containing neurons in the CeA using immunohistochemistry and electron microscopy. Ultrastructural analysis revealed that NE-labeled axon terminals form synapses with CRF- and DYN-containing neurons in the CeA. Semi-quantitative analysis showed that approximately 31 % of NET-labeled axon terminals targeted CeA neurons that co-expressed DYN and CRF. As a major source of CRF innervation to the LC, it is also not known whether CRF-containing CeA neurons are directly targeted by noradrenergic afferents. To test this, retrograde tract tracing using FluoroGold from the LC was combined with immunocytochemical detection of CRF and NET in the CeA. Our results revealed a population of LC-projecting CRF-containing CeA neurons that are directly innervated by NE afferents. Analysis showed that approximately 34 % of NET-labeled axon terminals targeted LC-projecting CeA neurons that contain CRF. Taken together, these results indicate significant interactions between NE, CRF and DYN in this critical limbic region and reveal direct synaptic interactions of NE with amygdalar CRF that influence the LC-NE arousal system. PMID:24271021
Synaptic plasticity in the auditory system: a review.
Friauf, Eckhard; Fischer, Alexander U; Fuhr, Martin F
Synaptic transmission via chemical synapses is dynamic, i.e., the strength of postsynaptic responses may change considerably in response to repeated synaptic activation. Synaptic strength is increased during facilitation, augmentation and potentiation, whereas a decrease in synaptic strength is characteristic for depression and attenuation. This review attempts to discuss the literature on short-term and long-term synaptic plasticity in the auditory brainstem of mammals and birds. One hallmark of the auditory system, particularly the inner ear and lower brainstem stations, is information transfer through neurons that fire action potentials at very high frequency, thereby activating synapses >500 times per second. Some auditory synapses display morphological specializations of the presynaptic terminals, e.g., calyceal extensions, whereas other auditory synapses do not. The review focuses on short-term depression and short-term facilitation, i.e., plastic changes with durations in the millisecond range. Other types of short-term synaptic plasticity, e.g., posttetanic potentiation and depolarization-induced suppression of excitation, will be discussed much more briefly. The same holds true for subtypes of long-term plasticity, like prolonged depolarizations and spike-time-dependent plasticity. We also address forms of plasticity in the auditory brainstem that do not comprise synaptic plasticity in a strict sense, namely short-term suppression, paired tone facilitation, short-term adaptation, synaptic adaptation and neural adaptation. Finally, we perform a meta-analysis of 61 studies in which short-term depression (STD) in the auditory system is opposed to short-term depression at non-auditory synapses in order to compare high-frequency neurons with those that fire action potentials at a lower rate. This meta-analysis reveals considerably less STD in most auditory synapses than in non-auditory ones, enabling reliable, failure-free synaptic transmission even at frequencies >100 Hz. Surprisingly, the calyx of Held, arguably the best-investigated synapse in the central nervous system, depresses most robustly. It will be exciting to reveal the molecular mechanisms that set high-fidelity synapses apart from other synapses that function much less reliably. PMID:25896885
Role of laryngeal afferents in cough.
Sant'Ambrogio, G; Sant'Ambrogio, F B
The superior laryngeal nerve (SLN) is the main source of laryngeal afferent activity. A clear respiratory modulation can be noted when recording from the peripheral cut end of this nerve in several mammalian species. This modulation is due to three types of sensory endings: cold, pressure and 'drive' receptors. Although respiratory-modulated receptors play an important role in the function of the upper airway, they are not generally viewed as a primary factor in the elicitation of cough. Other more likely candidates for this role are thought to be the so-called 'irritant' endings. These are receptors that do not discharge in close association with the breathing cycle, but are usually silent or randomly active in control conditions. However, they are promptly recruited when the laryngeal mucosa is exposed to mechanical and/or chemical irritation. In fact, these receptors respond to well recognized tussigenic stimuli and are therefore thought to provide the triggering mechanisms for the cough reflex from the larynx. Endings with similar characteristics are also found in the most proximal areas of the tracheo-bronchial tree. On the basis of their response to irritants, these receptors are identified under the common denomination of 'irritant receptors'. However, within this category of endings we find a wide range of distinctive characteristics, be this in terms of responsiveness to water solutions of various osmolarity and composition or to particular responses to substances produced within the body (autacoids) or experimentally administered. PMID:9232668
Mast cells drive mesenteric afferent signalling during acute intestinal ischaemia.
Jiang, Wen; Kirkup, Anthony J; Grundy, David
Acute intestinal ischaemia stimulates visceral afferent nerves but the mechanisms responsible for this excitation are not fully understood. Mast cells may participate in this process as they are known to signal to mesenteric afferents during intestinal anaphylaxis and contribute to early inflammation and neuronal damage in response to cerebral ischaemia. We therefore hypothesised that mast cells are early responders to acute intestinal ischaemia and their activation initiates rapid signalling to the CNS via the excitation of mesenteric afferents. Primary afferent firing was recorded from a mesenteric nerve bundle supplying a segment of jejunum in anaesthetized adult rats. Acute focal ischaemia was produced by clamping theme senteric vessels for 8 min, and reperfusion followed removal of the vessel clip. Two episodes of ischaemia–reperfusion (I–R) separated by a 30 min interval were performed. Drugs or their vehicles were administered 10 min before the 2nd I–R episode. Ischaemia caused a reproducible, intense and biphasic afferent firing that was temporally dissociated from the concomitantly triggered complex pattern of intestinal motor activity. The L-type calcium channel blocker, nifedipine, significantly attenuated this afferent firing by a mechanism independent of its action on intestinal tone. Ischaemia-induced afferent firing was also abrogated by the mast cell stabilizer, doxantrazole, and the H1 histamine receptor antagonist, pyrilamine. In contrast, the nicotinic receptor antagonist, hexamethonium, and the N-type calcium channel toxin, ?-conotoxin GVIA, each reduced the ischaemia-evoked motor inhibition but not the concurrent afferent discharge. Similarly, the cyclooxygenase inhibitor, naproxen, had no effect on the ischaemic afferent response but reduced the intestinal tone shortly from the onset of ischaemia to the early period of reperfusion. These data support a critical role for mast cell-derived histamine in the direct chemoexcitation of mesenteric afferents during acute intestinal ischaemia, whereas enteric reflex mechanisms and cyclooxygenase products contribute primarily to ischaemia-induced changes in intestinal motility. Therefore, targeting mast cells may provide benefits in patients with abdominal pain resulting from an ischaemic insult to the gastrointestinal tract. PMID:21669977
Synaptic contacts impaired by styrene-7,8-oxide toxicity
Corsi, P. [Dip. di Farmacologia e Fisiologia Umana, Facolta di Medicina e Chirurgia, Universita degli Studi di Bari, 70124 Italy (Italy)], E-mail: firstname.lastname@example.com; D'Aprile, A. [Dip. di Medicina Interna e Pubblica, Facolta di Medicina e Chirurgia, Universita di Bari (Italy); Nico, B. [Dip. di Anatomia Umana e Istologia, Facolta di Medicina e Chirurgia, Universita di Bari (Italy); Costa, G.L. [Dip. di Anatomia, Farmacologia e Scienze Medico Forensi, Facolta di Medicina e Chirurgia, Universita di Parma (Italy); Assennato, G. [Dip. di Medicina Interna e Pubblica, Facolta di Medicina e Chirurgia, Universita di Bari (Italy)
Styrene-7,8-oxide (SO), a chemical compound widely used in industrial applications, is a potential hazard for humans, particularly in occupational settings. Neurobehavioral changes are consistently observed in occupationally exposed individuals and alterations of neurotransmitters associated with neuronal loss have been reported in animal models. Although the toxic effects of styrene have been extensively documented, the molecular mechanisms responsible for SO-induced neurotoxicity are still unclear. A possible dopamine-mediated effect of styrene neurotoxicity has been previously demonstrated, since styrene oxide alters dopamine neurotransmission in the brain. Thus, the present study hypothesizes that styrene neurotoxicity may involve synaptic contacts. Primary striatal neurons were exposed to styrene oxide at different concentrations (0.1-1 mM) for different time periods (8, 16, and 24 h) to evaluate the dose able to induce synaptic impairments. The expression of proteins crucial for synaptic transmission such as Synapsin, Synaptophysin, and RAC-1 were considered. The levels of Synaptophysin and RAC-1 decreased in a dose-dependent manner. Accordingly, morphological alterations, observed at the ultrastructural level, primarily involved the pre-synaptic compartment. In SO-exposed cultures, the biochemical cascade of caspases was activated affecting the cytoskeleton components as their target. Thus the impairments in synaptic contacts observed in SO-exposed cultures might reflect a primarily morphological alteration of neuronal cytoskeleton. In addition, our data support the hypothesis developed by previous authors of reactive oxygen species (ROS) initiating events of SO cytotoxicity.
IL-6 regulation of synaptic function in the CNS.
Gruol, Donna L
A growing body of evidence supports a role for glial-produced neuroimmune factors, including the cytokine IL-6, in CNS physiology and pathology. CNS expression of IL-6 has been documented in the normal CNS at low levels and at elevated levels in several neurodegenerative or psychiatric disease states as well as in CNS infection and injury. The altered CNS function associated with these conditions raises the possibility that IL-6 has neuronal or synaptic actions. Studies in in vitro and in vivo models confirmed this possibility and showed that IL-6 can regulate a number of important neuronal and synaptic functions including synaptic transmission and synaptic plasticity, an important cellular mechanism of memory and learning. Behavioral studies in animal models provided further evidence of an important role for IL-6 as a regulator of CNS pathways that are critical to cognitive function. This review summarizes studies that have lead to our current state of knowledge. In spite of the progress that has been made, there is a need for a greater understanding of the physiological and pathophysiological actions of IL-6 in the CNS, the mechanisms underlying these actions, conditions that induce production of IL-6 in the CNS and therapeutic strategies that could ameliorate or promote IL-6 actions. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID:25445486
Tensor Tympani Motoneurons Receive Mostly Excitatory Synaptic Inputs
The tensor tympani is a middle ear muscle that contracts in two different situations: in response to sound or during voluntary movements. To gain insight into the inputs and neural regulation of the tensor tympani, we examined the ultrastructure of synaptic terminals on labeled tensor tympani motoneurons (TTMNs) using transmission electron microscopy. Our sample of six TTMNs received 79 synaptic terminals that formed 126 synpases. Two types of synapses are associated with round vesicles and form asymmetric junctions (excitatory morphology). One of these types has vesicles that are large and round (Lg Rnd) and the other has vesicles that are smaller and round (Sm Rnd) and also contains at least one dense core vesicle. A third synapse type has inhibitory morphology because it forms symmetric synapses with pleomorphic vesicles (Pleo). These synaptic terminals can be associated with TTMN spines. Two other types of synapse are found on TTMNs but they are uncommon. Synaptic terminals of all types form multiple synapses but those from a single terminal are always the same type. Terminals with Lg Rnd vesicles formed the most synpases per terminal (avg. 2.73). Together, the synaptic terminals with Lg Rnd and Sm Rnd vesicles account for 62% of the terminals on TTMNs, and they likely represent the pathways driving the contractions in response to sound or during voluntary movements. Having a high proportion of excitatory inputs, the TTMN innervation is like that of stapedius motoneurons but proportionately different from other types of motoneurons. PMID:23165747
Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules.
Sacramento, Joăo; Wichert, Andreas; van Rossum, Mark C W
It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID:26046817
Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules
Sacramento, Joăo; Wichert, Andreas; van Rossum, Mark C. W.
It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID:26046817
Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis
Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua; Sabatini, Bernardo L
Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors. DOI: http://dx.doi.org/10.7554/eLife.01936.001 PMID:24843012
Stance-phase force on the opposite limb dictates swing-phase afferent presynaptic inhibition during locomotion
Hayes, Heather Brant; Chang, Young-Hui
Presynaptic inhibition is a powerful mechanism for selectively and dynamically gating sensory inputs entering the spinal cord. We investigated how hindlimb mechanics influence presynaptic inhibition during locomotion using pioneering approaches in an in vitro spinal cord–hindlimb preparation. We recorded lumbar dorsal root potentials to measure primary afferent depolarization-mediated presynaptic inhibition and compared their dependence on hindlimb endpoint forces, motor output, and joint kinematics. We found that stance-phase force on the opposite limb, particularly at toe contact, strongly influenced the magnitude and timing of afferent presynaptic inhibition in the swinging limb. Presynaptic inhibition increased in proportion to opposite limb force, as well as locomotor frequency. This form of presynaptic inhibition binds the sensorimotor states of the two limbs, adjusting sensory inflow to the swing limb based on forces generated by the stance limb. Functionally, it may serve to adjust swing-phase sensory transmission based on locomotor task, speed, and step-to-step environmental perturbations. PMID:22442562
Classification: Molecular & Synaptic Mechanisms
Lussier, Marc P.; Gu, Xinglong; Lu, Wei; Roche, Katherine W.
Controlling the density of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at synapses is essential for regulating the strength of excitatory neurotransmission. In particular, the phosphorylation of AMPARs is important for defining both synaptic expression and intracellular routing of receptors. Phosphorylation is a posttranslational modification known to regulate many cellular events and the C-termini of glutamate receptors are important targets. Recently, the first intracellular loop1 region of the GluA1 subunit of AMPARs was reported to regulate synaptic targeting through phosphorylation of S567 by Ca2+/calmodulin-dependent protein kinase II (CaMKII). Intriguingly, the loop1 region of all four AMPAR subunits contains many putative phosphorylation sites (S/T/Y), leaving the possibility that other kinases may regulate AMPAR surface expression via phosphorylation of the loop regions. To explore this hypothesis, we used in vitro phosphorylation assays with a small panel of purified kinases and found that casein kinase 2 (CK2) phosphorylates the GluA1 and GluA2 loop1 regions, but not GluA3 or GluA4. Interestingly, when we reduced the endogenous expression of CK2 using a specific shRNA against the regulatory subunit CK2?, we detected a reduction of GluA1 surface expression, whereas GluA2 was unchanged. Furthermore, we identified S579 of GluA1 as a substrate of CK2, and the expression of GluA1 phospho-deficient mutants in hippocampal neurons displayed reduced surface expression. Therefore, our study identifies CK2 as a regulator of GluA1 surface expression by phosphorylating the intracellular loop1 region. PMID:24712994
Coordinate Synaptic Mechanisms Contributing to Olfactory Cortical Adaptation
Best, Aaron R.; Wilson, Donald A.
Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this nonassociative neural plasticity using in vivo and in vitro preparations and to determine its role in cortical odor adaptation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants. The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10–20 sec of the post-train recovery period and a longer lasting (~120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-?-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the ?-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the ? (15–35 Hz) spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo. PMID:14736851
Semicircular Canal Geometry, Afferent Sensitivity And Animal Behavior
Hullar, Timothy A.
The geometry of the semicircular canals has been used in evolutionary studies to predict the behaviors of extinct animals. These predictions have relied on an assumption that the responses of the canals can be determined from their dimensions, and that an organism's behavior can be determined from these responses. However, the relationship between a canal's sensitivity and its size is not well known. An intraspecies comparison among canal responses in each of three species (cat, squirrel monkey, and pigeon) was undertaken to evaluate various models of canal function and determine how their dimensions may be related to afferent physiology. All models predicted the responses of the cat afferents, but the models performed less well for squirrel monkey and pigeon. Possible causes for this discrepancy include incorrectly assuming that afferent responses accurately represent canal function, or errors in current biophysical models of the canals. These findings leave open the question as to how reliably canal anatomy can be used to estimate afferent responses and how closely afferent responses are related to behavior. Other labyrinthine features—such as orientation of the horizontal canal, which is reliably held near earth-horizontal across many species—may be better to use when extrapolating the posture and related behavior of extinct animals from labyrinthine morphology. PMID:16550591
Low-Dimensional Sensory Feature Representation by Trigeminal Primary Afferents
Bale, Michael R.; Davies, Kyle; Freeman, Oliver J.; Ince, Robin A. A.
In any sensory system, the primary afferents constitute the first level of sensory representation and fundamentally constrain all subsequent information processing. Here, we show that the spike timing, reliability, and stimulus selectivity of primary afferents in the whisker system can be accurately described by a simple model consisting of linear stimulus filtering combined with spike feedback. We fitted the parameters of the model by recording the responses of primary afferents to filtered, white noise whisker motion in anesthetized rats. The model accurately predicted not only the response of primary afferents to white noise whisker motion (median correlation coefficient 0.92) but also to naturalistic, texture-induced whisker motion. The model accounted both for submillisecond spike-timing precision and for non-Poisson spike train structure. We found substantial diversity in the responses of the afferent population, but this diversity was accurately captured by the model: a 2D filter subspace, corresponding to different mixtures of position and velocity sensitivity, captured 94% of the variance in the stimulus selectivity. Our results suggest that the first stage of the whisker system can be well approximated as a bank of linear filters, forming an overcomplete representation of a low-dimensional feature space. PMID:23864687
Activity-Independent Prespecification of Synaptic Partners in the Visual Map of Drosophila
Hiesinger, P. Robin; Zhai, R. Grace; Zhou, Yi; Koh, Tong-Wey; Mehta, Sunil Q.; Schulze, Karen L.; Cao, Yu; Verstreken, Patrik; Clandinin, Thomas R.; Fischbach, Karl-Friedrich; Meinertzhagen, Ian A.; Bellen, Hugo J.
Summary Specifying synaptic partners and regulating synaptic numbers are at least partly activity-dependent processes during visual map formation in all systems investigated to date [1–5]. In Drosophila, six photo-receptors that view the same point in visual space have to be sorted into synaptic modules called cartridges in order to form a visuotopically correct map [6, 7]. Synapse numbers per photoreceptor terminal and cartridge are both precisely regulated [8–10]. However, it is unknown whether an activity-dependent mechanism or a genetically encoded developmental program regulates synapse numbers. We performed a large-scale quantitative ultrastructural analysis of photoreceptor synapses in mutants affecting the generation of electrical potentials (norpA, trp;trpl), neurotransmitter release (hdc, syt), vesicle endocytosis (synj), the trafficking of specific guidance molecules during photoreceptor targeting (sec15), a specific guidance receptor required for visual map formation (Dlar), and 57 other novel synaptic mutants affecting 43 genes. Remarkably, in all these mutants, individual photoreceptors form the correct number of synapses per presynaptic terminal independently of cartridge composition. Hence, our data show that each photoreceptor forms a precise and constant number of afferent synapses independently of neuronal activity and partner accuracy. Our data suggest cell-autonomous control of synapse numbers as part of a developmental program of activity-independent steps that lead to a "hardwired" visual map in the fly brain. PMID:16979562
Memory stability and synaptic plasticity
Billings, Guy
Numerous experiments have demonstrated that the activity of neurons can alter the strength of excitatory synapses. This synaptic plasticity is bidirectional and synapses can be strengthened (potentiation) or weakened ...
Input-specific maturation of synaptic dynamics of parvalbumin interneurons in primary visual cortex.
Lu, Jiangteng; Tucciarone, Jason; Lin, Ying; Huang, Z Josh
Cortical networks consist of local recurrent circuits and long-range pathways from other brain areas. Parvalbumin-positive interneurons (PVNs) regulate the dynamic operation of local ensembles as well as the temporal precision of afferent signals. The synaptic recruitment of PVNs that support these circuit operations is not well-understood. Here we demonstrate that the synaptic dynamics of PVN recruitment in mouse visual cortex are customized according to input source with distinct maturation profiles. Whereas the long-range inputs to PVNs show strong short-term depression throughout postnatal maturation, local inputs from nearby pyramidal neurons progressively lose such depression. This enhanced local recruitment depends on PVN-mediated reciprocal inhibition and results from both pre- and postsynaptic mechanisms, including calcium-permeable AMPA receptors at PVN postsynaptic sites. Although short-term depression of long-range inputs is well-suited for afferent signal detection, the robust dynamics of local inputs may facilitate rapid and proportional PVN recruitment in regulating local circuit operations. PMID:25385583
Input-specific maturation of synaptic dynamics of parvalbumin interneurons in primary visual cortex
Lu, Jiangteng; Tucciarone, Jason; Lin, Ying; Huang, Z. Josh
Cortical networks consist of local recurrent circuits and long-range pathways from other brain areas. Parvalbumin-positive interneurons (PVNs) regulate the dynamic operation of local ensembles as well as the temporal precision of afferent signals. The synaptic recruitment of PVNs that support these circuit operations is not well-understood. Here we demonstrate that the synaptic dynamics of PVN recruitment in mouse visual cortex are customized according to input source with distinct maturation profiles. Whereas the long-range inputs to PVNs show strong short-term depression throughout postnatal maturation, local inputs from nearby pyramidal neurons progressively lose such depression. This enhanced local recruitment depends on PVN-mediated reciprocal inhibition and results from both pre- and postsynaptic mechanisms, including calcium-permeable AMPA receptors at PVN postsynaptic sites. Although short-term depression of long-range inputs is well-suited for afferent signal detection, the robust dynamics of local inputs may facilitate rapid and proportional PVN recruitment in regulating local circuit operations. PMID:25385583
Synaptic Alterations in Genetic Mouse Models of Huntington's and Parkinson's Diseases: Is there a Common Thread?
Carlos Cepeda; Nanping Wu; Véronique M. André; Michael S. Levine
The principal function of neurons is to communicate messages via the release of neurotransmitters, neuromodulators and trophic\\u000a factors. Impaired synaptic transmission leads to cognitive and motor abnormalities. Huntingtin, ?-synuclein and parkin play\\u000a an important role in vesicle transport and synaptic transmission, so that mutations in these proteins impair neuronal communication\\u000a and lead to a characteristic phenotype. Understanding the function of
Cortical Synaptic Inhibition Declines during Auditory Learning.
Sarro, Emma C; von Trapp, Gardiner; Mowery, Todd M; Kotak, Vibhakar C; Sanes, Dan H
Auditory learning is associated with an enhanced representation of acoustic cues in primary auditory cortex, and modulation of inhibitory strength is causally involved in learning. If this inhibitory plasticity is associated with task learning and improvement, its expression should emerge and persist until task proficiency is achieved. We tested this idea by measuring changes to cortical inhibitory synaptic transmission as adult gerbils progressed through the process of associative learning and perceptual improvement. Using either of two procedures, aversive or appetitive conditioning, animals were trained to detect amplitude-modulated noise and then tested daily. Following each training session, a thalamocortical brain slice was generated, and inhibitory synaptic properties were recorded from layer 2/3 pyramidal neurons. Initial associative learning was accompanied by a profound reduction in the amplitude of spontaneous IPSCs (sIPSCs). However, sIPSC amplitude returned to control levels when animals reached asymptotic behavioral performance. In contrast, paired-pulse ratios decreased in trained animals as well as in control animals that experienced unpaired conditioned and unconditioned stimuli. This latter observation suggests that inhibitory release properties are modified during behavioral conditioning, even when an association between the sound and reinforcement cannot occur. These results suggest that associative learning is accompanied by a reduction of postsynaptic inhibitory strength that persists for several days during learning and perceptual improvement. PMID:25904785
Nicotinic acetylcholine receptor-mediated synaptic potentials in rat neocortex
Z. G. Chu; F. M. Zhou; J. J. Hablitz
In the neocortex, fast excitatory synaptic transmission can typically be blocked by using excitatory amino acid (EAA) receptor antagonists. In recordings from layer II\\/III neocortical pyramidal neurons, we observed an evoked excitatory postsynaptic potential (EPSP) or current (EPSC) in the presence of EAA receptor antagonists (40–100 ?M D-APV+20 ?M CNQX, or 5 mM kynurenic acid) plus the GABAA-receptor antagonist bicuculline
Afferent loop obstruction after gastrectomy simulating acute pancreatitis.
Alawneh, I
After gastrectomy and Billroth II anastomosis, if the afferent loop is too long, it may kink and herniate, resulting in obstruction. If it is too short, it may produce acute angulation with obstruction. This condition often simulates acute pancreatitis when the amylase level in urine and serum is increased. Three cases of afferent loop obstruction are reported. The patient who did not undergo laparotomy died; the other two were operated on and survived. The diagnosis, etiology and treatment of these complications are discussed, and similar cases reported in the literature are cited. PMID:6161096
Volume transmission signalling via astrocytes
Hirase, Hajime; Iwai, Youichi; Takata, Norio; Shinohara, Yoshiaki; Mishima, Tsuneko
The influence of astrocytes on synaptic function has been increasingly studied, owing to the discovery of both gliotransmission and morphological ensheathment of synapses. While astrocytes exhibit at best modest membrane potential fluctuations, activation of G-protein coupled receptors (GPCRs) leads to a prominent elevation of intracellular calcium which has been reported to correlate with gliotransmission. In this review, the possible role of astrocytic GPCR activation is discussed as a trigger to promote synaptic plasticity, by affecting synaptic receptors through gliotransmitters. Moreover, we suggest that volume transmission of neuromodulators could be a biological mechanism to activate astrocytic GPCRs and thereby to switch synaptic networks to the plastic mode during states of attention in cerebral cortical structures. PMID:25225097
Retinal waves regulate afferent terminal targeting in the early visual pathway.
Failor, Samuel; Chapman, Barbara; Cheng, Hwai-Jong
Current models of retinogeniculate development have proposed that connectivity between the retina and the dorsal lateral geniculate nucleus (dLGN) is established by gradients of axon guidance molecules, to allow initial coarse connections, and by competitive Hebbian-like processes, to drive eye-specific segregation and refine retinotopy. Here we show that when intereye competition is eliminated by monocular enucleation, blocking cholinergic stage II retinal waves disrupts the intraeye competition-mediated expansion of the retinogeniculate projection and results in the permanent disorganization of its laminae. This disruption of stage II retinal waves also causes long-term impacts on receptive field size and fine-scale retinotopy in the dLGN. Our results reveal a novel role for stage II retinal waves in regulating retinogeniculate afferent terminal targeting by way of intraeye competition, allowing for correct laminar patterning and the even allocation of synaptic territory. These findings should contribute to answering questions regarding the role of neural activity in guiding the establishment of neural circuits. PMID:26038569
Miniature EPSPs and sensory encoding in the primary afferents of the vestibular lagena of the toadfish, Opsanus tau
NASA Technical Reports Server (NTRS)
Locke, R.; Vautrin, J.; Highstein, S.
The synaptic activity transmitted from vestibular hair cells of the lagena to primary afferent neurons was recorded in vitro using sharp, intracellular microelectrodes. At rest, the activity was composed of miniature excitatory postsynaptic potentials (mEPSPs) at frequencies from 5 to 20/s and action potentials (APs) at frequencies betwen 0 and 10/s. mEPSPs recorded from a single fiber displayed a large variability. For mEPSPs not triggering APs, amplitudes exhibited an average coefficient of variance (CV) of 0.323 and rise times an average CV of 0.516. APs were only triggered by mEPSPs with larger amplitudes (estimated 4-6 mV) and/or steeper maximum rate of rise (10.9 mV/ms, +/- 3.7 SD, n=4 experiments) compared to (3.50 mV/ms, +/-0.07 SD, n=6 experiments) for nontriggering mEPSPs. The smallest mEPSPs showed a fast rise time (0.99 ms between 10% and 90% of peak amplitude) and limited variability across fibers (CV:0.18) confirming that they were not attenuated signals, but rather represented single-transmitter discharges (TDs). The mEPSP amplitude and rise-time relationship suggests that many mEPSPs represented several, rather than a single pulse of secretion of TDs. According to the estimated overall TD frequency, the coincidence of TDs contributing to the same mEPSP were not statistically independent, indicating a positive interaction between TDs that is reminiscent of the way subminiature signals group to form miniature signals at the neuromuscular junction. Depending on the duration and intensity of efferent stimulation, a complete block of AP initiation occurred either immediately or after a delay of a few seconds. Efferent stimulation did not significantly change AP threshold level, but abruptly decreased mEPSP frequency to a near-complete block that followed the block of APs. Maximum mEPSP rate of rise decreased during, and recovered progressively after, efferent stimulation. After termination of efferent stimulation, mEPSP amplitude did not recover instantly and for a few seconds the amplitude distribution of synaptic events showed fewer large-amplitude events than during the control period. This confirms that mEPSP amplitude and rate of rise properties, which are critical for triggering afferent APs, are modified by efferent activity. The depression of afferent AP firing during efferent stimulation corresponded to a decrease in mEPSP frequency and, to a lesser extent, a decrease in mEPSP amplitude and rate of rise, suggesting, a decrease in the level of interaction among TDs contibuting to a mEPSP.
Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity
García-Morales, Victoria; Montero, Fernando; González-Forero, David; Rodríguez-Bey, Guillermo; Gómez-Pérez, Laura; Medialdea-Wandossell, María Jesús; Domínguez-Vías, Germán; García-Verdugo, José Manuel; Moreno-López, Bernardo
Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/G?i/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAA?2 subunit through the LPA1/G?12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAA?2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron. PMID:25996636
Estrogen Promotes Learning Related Plasticity by Modifying the Synaptic Cytoskeleton
Kramár, Enikö A.; Babayan, Alex H.; M.Gall, Christine; Lynch, Gary
Estrogen's acute, facilitatory effects on glutamatergic transmission and long-term potentiation (LTP) provide a potential explanation for the steroid's considerable influence on behavior. Recent work has identified mechanisms underlying these synaptic actions. Brief infusion of 17?-estradiol (E2) into adult male rat hippocampal slices triggers actin polymerization within dendritic spines via a signaling cascade beginning with the GTPase RhoA and ending with inactivation of the filament severing protein cofilin. Blocking this sequence, or actin polymerization itself, eliminates E2's effects on synaptic physiology. Notably, the theta burst stimulation used to induce LTP activates the same signaling pathway as E2 plus events that stabilize the reorganization of the sub-synaptic cytoskeleton. These observations suggest that E2 elicits a partial form of LTP, resulting in an increase of fast EPSP's and a reduction in the threshold for lasting synaptic changes. While E2's effects on the cytoskeleton could be direct, results described here indicate that the hormone activates synaptic TrkB receptors for Brain Derived Neurotrophic Factor, a releasable neurotrophin that stimulates the RhoA to cofilin pathway. It is therefore possible that E2 acts via transactivation of neighboring receptors to modify the composition and structure of excitatory contacts. Finally, there is the question of whether a loss of acute synaptic actions contributes to the memory problems associated with estrogen depletion. Initial tests found that ovariectomy in middle-aged rats disrupts RhoA signaling, actin polymerization, and LTP consolidation. Acute applications of E2 reversed these defects, a result consistent with the idea that disturbances to actin management are one cause of behavioral effects that emerge with reductions in steroid levels. PMID:23103216
Models of brain injury and alterations in synaptic plasticity.
Albensi, B C
Animal models are crucial for understanding human pathophysiological processes and for understanding how connections are injured, lost, or even regenerated and/or repaired. When animal models are used in conjunction with theoretical computational models, an ideal combination is achieved that potentially yields insight and encourages the formation of new theories concerning connectionism, cognitive functioning, and synaptic mechanisms. Mechanisms regulating glutamate receptor activation and intracellular calcium levels are important for normal synaptic transmission. These mechanisms (and others) are also critical during and after brain injury when the potential exists for these mechanisms to function pathologically. Interestingly enough, the regulation of glutamate receptor activation and intracellular calcium levels is also involved in normal processes of neuronal and synaptic plasticity. In addition, studies have shown that neurotrophins and cytokines, which are released after brain injury, can be neuroprotective and may also be important in synaptic plasticity. Furthermore, synaptic plasticity is a phenomenon thought by many to be necessary for memory encoding. If this is the case, then research described in this review has significant scientific merit concerning plasticity and memory and clinical benefit for understanding pathophysiologic processes associated with brain injury and memory impairment. This paper reviews the application of experimental animal models of brain injury for simulating conditions of stroke, trauma, and epilepsy (and/or seizure generation) and the associated cellular mechanisms of brain injury. The paper also briefly addresses the advantage of using computational models in combination with experimental models for hypothesis building and for aiding in the interpretation of empirical data. Finally, it reviews studies concerning brain injury and synaptic plasticity. PMID:11494362
Research report Persistence of PAD and presynaptic inhibition of muscle spindle afferents after peripheral nerve crush
M. Enriquez-Denton; E. Manjarrez; P. Rudomin
Two to twelve weeks after crushing a muscle nerve, still before the damaged afferents reinnervate the muscle receptors, conditioning stimulation of group I fibers from flexor muscles depolarizes the damaged afferents (M. Enriquez, I. Jimenez, P. Rudomin, Changes in PAD patterns of group I muscle afferents after a peripheral nerve crush. Exp. Brain Res., 107 (1996), 405-420). It is not
K. G. PEARSON; R. K. S. WONG; C. R. FOURTNERf
SUMMARY 1. The trochanteral hair-plate afferents in the metathoracic leg of the cock- roach, Periplaneta americana, were stimulated electrically and at the same time intracellular recordings were made from either motoneurones, inter- neurones or afferent terminals within the metathoracic ganglion. 2. Activity in the hair-plate afferents evoked short latency excitatory postsynaptic potentials (EPSPs) in femur extensor motoneurones and inhibitory postsynaptic
Unmyelinated afferents in human skin and their responsiveness to low temperature
Mario Campero; Hugh Bostock
In humans, there are different types of cutaneous cold-sensitive afferents responsible for cold sensation and cold pain. Innocuous cold is primarily mediated by a population of slow A delta afferents, based on psychophysical and neurophysiological studies. Noxious cold (usually below 15°C) is mediated, at least in part, by polymodal nociceptors. There is also a population of unmyelinated afferents responsive to
THE JOURNAL OF COMPARATIVENEUROLOGY 231:435-445 (198.5) Afferent Influences on Brain Stem
Rubel, Edwin
THE JOURNAL OF COMPARATIVENEUROLOGY 231:435-445 (198.5) Afferent Influences on Brain Stem Auditory, more dramatic changes often are observed following affer- ent manipulation in young animals than stem auditory areas that receive afferents from the eighth nerve. Other investigators have examined mor
Tuning of Spinal Networks to Frequency Components of Spike Trains in Individual Afferents
H. Richard Koerber; Andrew W. Seymour; Lorne M. Mendell
Cord dorsum potentials (CDPs) evoked by primary afferent fiber stimulation reflect the response of postsynaptic dorsal horn neurons. The properties of these CDPs have been shown to vary in accordance with the type of primary afferent fiber stimulated. The purpose of the present study was to deter- mine the relationships between frequency modulation of the afferent input trains, the amplitude
Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord
Kaas, Jon H.; Qi, Hui-Xin; Burish, Mark; Gharbawie, Omar; Onifer, Stephen M.; Massey, James M.
The failure of injured axons to regenerate following spinal cord injury deprives brain neurons of their normal sources of activation. These injuries also result in the reorganization of affected areas of the central nervous system that is thought to drive both the ensuing recovery of function and the formation of maladaptive neuronal circuitry. Better understanding of the physiological consequences of novel synaptic connections produced by injury and the mechanisms that control their formation are important to the development of new successful strategies for the treatment of patients with spinal cord injuries. Here we discuss the anatomical, physiological and behavioral changes that take place in response to injury-induced plasticity after damage to the dorsal column pathway in rats and monkeys. Complete section of the dorsal columns of the spinal cord at a high cervical level in monkeys and rats interrupts the ascending axon branches of low threshold mechanoreceptor afferents subserving the forelimb and the rest of the lower body. Such lesions render the corresponding part of the somatotopic representation of primary somatosensory cortex totally unresponsive to tactile stimuli. There are also behavioral consequences of the sensory loss, including an impaired use of the hand/forelimb in manipulating small objects. In monkeys, if some of the afferents from the hand remain intact after dorsal column lesions, these remaining afferents extensively reactivate portions of somatosensory cortex formerly representing the hand. This functional reorganization develops over a postoperative period of one month, during which hand use rapidly improves. These recoveries appear to be mediated, at least in part, by the sprouting of preserved afferents within the cuneate nucleus of the dorsal column-trigeminal complex. In rats, such functional collateral sprouting has been promoted by the post-lesion digestion of the perineuronal net in the cuneate nucleus. Thus, this and other therapeutic strategies have the potential of enhancing sensorimotor recoveries after spinal cord injuries in humans. PMID:17692844
Synaptic physiology of central CRH system
Gallagher, Joel P.; Orozco-Cabal, Luis F.; Liu, Jie; Shinnick-Gallagher, Patricia
Corticotropin Releasing Hormone (CRH) or Corticotropin Releasing Factor (CRF) and its family of related naturally occurring endogenous peptides and receptors are becoming recognized for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term 'CRH' has been displaced by 'CRF' (Guillemin 2005). However, to maintain uniformity among contributions to this special issue we have used the original term, CRH. The term 'CRF' has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee (Hauger R.L. et al. 2003) to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identified (Orozco-Cabal et al. 2006). It is especially noteworthy that since the synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia (Fischbach 2007), and neurological disorders, e.g., Alzheimer's disease (Bell and Cuello 2006), we suggest that "THE STRESSED SYNAPSE" has been overlooked (c.f., Kim and Diamond 2002; Radley and Morrison 2005) as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial prefrontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission. PMID:18342852
Cerebellar afferents in the frogs, Rana esculenta and Rana temporaria
B. G. Grover; U. Grüsser-Cornehls
Afferents to the cerebellum in frogs (Rana esculenta, Rana temporaria) were studied by use of retrograde transport of horseradish peroxidase. Following injections restricted to the molecular layer of the cerebellum cell labelling was found in the contralateral inferior olive and the ventral portion of the caudal medullary raphe. Injections involving the granular layer resulted in labelling in the ventral horn
Afferent Input Regulates the Formation of Distal Dendritic Branches
Libersat, Frederic
organs called cerci provide the major Grant sponsor: Israel Academy of Sciences and Humanities; Grant numAfferent Input Regulates the Formation of Distal Dendritic Branches ADI MIZRAHI* AND FREDERIC LIBERSAT Zlotowski Center for Neuroscience and Department of Life Sciences, Ben-Gurion University
Intravesical Oxybutynin: A Local Anesthetic Effect on Bladder C Afferents
PurposeIntravesical oxybutynin is used to control bladder overactivity in patients who are refractory to or cannot tolerate oxybutynin given orally. Although it is clinically effective, the mode of action of intravesical oxybutynin remains unclear. We tested the influence of intravesical oxybutynin on single fiber pelvic nerve afferents from the rat bladder.
Synaptic calcium regulation in hair cells of the chicken basilar papilla.
Im, Gi Jung; Moskowitz, Howard S; Lehar, Mohammed; Hiel, Hakim; Fuchs, Paul Albert
Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ?100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh-evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents ("minis") resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long-term signaling. PMID:25505321
Synaptic Calcium Regulation in Hair Cells of the Chicken Basilar Papilla
Im, Gi Jung; Moskowitz, Howard S.; Lehar, Mohammed; Hiel, Hakim
Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ?100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh-evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents ("minis") resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long-term signaling. PMID:25505321
A correlated nickelate synaptic transistor
NASA Astrophysics Data System (ADS)
Shi, Jian; Ha, Sieu D.; Zhou, You; Schoofs, Frank; Ramanathan, Shriram
Inspired by biological neural systems, neuromorphic devices may open up new computing paradigms to explore cognition, learning and limits of parallel computation. Here we report the demonstration of a synaptic transistor with SmNiO3, a correlated electron system with insulator-metal transition temperature at 130°C in bulk form. Non-volatile resistance and synaptic multilevel analogue states are demonstrated by control over composition in ionic liquid-gated devices on silicon platforms. The extent of the resistance modulation can be dramatically controlled by the film microstructure. By simulating the time difference between postneuron and preneuron spikes as the input parameter of a gate bias voltage pulse, synaptic spike-timing-dependent plasticity learning behaviour is realized. The extreme sensitivity of electrical properties to defects in correlated oxides may make them a particularly suitable class of materials to realize artificial biological circuits that can be operated at and above room temperature and seamlessly integrated into conventional electronic circuits.
Mechanism of synaptic vesicle retrieval in epilepsy
Clayton, Emma Louise
Excessive release of neurotransmitter is a characteristic of epileptogenic cells. A number of lines of evidence implicate defects in the synaptic vesicle cycle as a cause of this excessive release. Synaptic vesicles are ...
Integration of visual and proprioceptive afferents in kinesthesia.
Guerraz, M; Provost, S; Narison, R; Brugnon, A; Virolle, S; Bresciani, J-P
Proprioceptive signals are of prime importance in kinesthesia. However, in conditions of visuo-proprioceptive conflicts, strong visual-evoked biases can be observed. In three experiments, we parsed the interaction between visual and proprioceptive afferents using the 'mirror box' paradigm. Participants' left arm, the image of which was reflected in a mirror, was passively moved into flexion/extension or remained static. In Experiment 1 proprioceptive afferents of the unseen static right arm were masked with diffuse arm vibration. In Experiments 2 and 3, afferent signals were enhanced by muscle vibration of biceps or triceps stretch receptors. Illusory arm movements were evaluated with subjective reports and matching adjustments. Results revealed that participants did not experience kinesthetic illusions when the mirror reflected the image of a static arm while proprioceptive afferents conveyed signals of a moving arm (Experiment 2). In this specific case, vision apparently contributed much more strongly to the final percept than proprioceptive signals. However, in most circumstances, the percept reflected integration of both afferent signals (Experiments 1-3). For instance, when both sensory channels conveyed signals of arm displacement but in the opposite direction, kinesthetic illusions occurred but were either proprioceptively (vibration illusion) or visually driven (mirror illusion), according to individual sensorial preferences (Experiments 2 and 3). These results indicate that kinesthesia is the product of cooperative integration processes in which the final percept strongly depends on the experimental conditions as well as sensorial preferences. The observed changes in the relative contribution of each input across experimental conditions likely reflect reliability-dependent weights. PMID:22864182
Visual input controls the functional activity of goldfish Mauthner neuron through the reciprocal synaptic mechanism.
Moshkov, Dmitry A; Shtanchaev, Rashid S; Mikheeva, Irina B; Bezgina, Elena N; Kokanova, Nadezhda A; Mikhailova, Gulnara Z; Tiras, Nadezhda R; Pavlik, Lyubov' L
Goldfish are known to exhibit motor asymmetry due to functional asymmetry of their Mauthner neurons that induce the turns to the right or left during free swimming. It has been previously found that if the less active neuron is subjected to prolonged aimed visual stimulation via its ventral dendrite, the motor asymmetry of goldfish is inverted, testifying that this neuron becomes functionally dominant, while the size of the ventral dendrite under these conditions is reduced 2-3 times compared to its counterpart in mirror neuron. Earlier it has been also revealed that training optokinetic stimulation induces adaptation, a substantial resistance of both fish motor asymmetry and morphofunctional state of Mauthner neurons against prolonged optokinetic stimulation. The aim of this work was to study the cellular mechanisms of the effect of an unusual visual afferent input on goldfish motor asymmetry and Mauthner neuron function in norm and under adaptation. It was shown that serotonin applied onto Mauthner neurons greatly reduces their activity whereas its antagonist ondansetron increases it. Against the background of visual stimulation, serotonin strengthens functional asymmetry between neurons whereas ondansetron smoothes it. Taken together these data suggest the involvement of serotonergic excitatory synaptic transmission in the regulation of Mauthner neurons by vision. Ultrastructural study of the ventral dendrites after prolonged optokinetic stimulation has revealed depletions of numeral axo-axonal synapses with specific morphology, identified by means of immunogold label as serotonergic ones. These latter in turn are situated mainly on shaft boutons, which according to specific ultrastructural features are assigned to axo-dendritic inhibitory synapses. Thus, the excitatory serotonergic synapses seem to affect Mauthner neuron indirectly through inhibitory synapses. Further, it was morphometrically established that adaptation is accompanied by the significant decrease of active zones dimensions in both serotonergic and inhibitory synapses. Finally, it was determined in model experiments that the interaction of globular actin with glycine, a main inhibitory neurotransmitter supposedly directly and chronically affecting the ventral dendrite, results in actin filaments formation. It is assumed that glycine-induced cytosolic actin polymerization is a cause of reduction in the ventral dendrite size under stimulation. Thus, it was established that a rather small group of synapses situated on an individual dendrite of the neuron determines the execution of the important form of animal behavior. PMID:23621454
Expression of transient receptor potential ankyrin 1 (TRPA1) in the rat trigeminal sensory afferents and spinal dorsal horn.
Kim, Yun Sook; Son, Jae Youn; Kim, Tae Heon; Paik, Sang Kyoo; Dai, Yi; Noguchi, Koichi; Ahn, Dong Kuk; Bae, Yong Chul
Transient receptor potential ankyrin 1 (TRPA1), responding to noxious cold and pungent compounds, is implicated in the mediation of nociception, but little is known about the processing of the TRPA1-mediated nociceptive information within the trigeminal sensory nuclei (TSN) and the spinal dorsal horn (DH). To address this issue, we characterized the TRPA1-positive (+) neurons in the trigeminal ganglion (TG) and investigated the distribution of TRPA1(+) afferent fibers and their synaptic connectivity within the rat TSN and DH by using light and electron microscopic immunohistochemistry. In the TG, TRPA1 was expressed in unmyelinated and small myelinated axons and also occasionally in large myelinated axons. Many TRPA1(+) neurons costained for the marker for peptidergic neurons substance P (26.8%) or the marker for nonpeptidergic neurons IB4 (44.5%). In the CNS, small numbers of axons and terminals were immunopositive for TRPA1 throughout the rostral TSN, in contrast to the dense network of positive fibers and terminals in the superficial laminae of the trigeminal caudal nucleus (Vc) and DH. The TRPA1(+) terminals contained clear round vesicles, were presynaptic to one or two dendrites, and rarely participated in axoaxonic contacts, suggesting involvement in relatively simple synaptic circuitry with a small degree of synaptic divergence and little presynaptic modulation. Immunoreactivity for TRPA1 was also occasionally observed in postsynaptic dendrites. These results suggest that TRPA1-dependent orofacial and spinal nociceptive input is processed mainly in the superficial laminae of the Vc and DH in a specific manner and may be processed differently between the rostral TSN and Vc. PMID:20034057
The Influence of Synaptic Size on AMPA Receptor Activation: A Monte Carlo Model
Montes, Jesus; Peńa, Jose M.; DeFelipe, Javier; Herreras, Oscar; Merchan-Perez, Angel
Physiological and electron microscope studies have shown that synapses are functionally and morphologically heterogeneous and that variations in size of synaptic junctions are related to characteristics such as release probability and density of postsynaptic AMPA receptors. The present article focuses on how these morphological variations impact synaptic transmission. We based our study on Monte Carlo computational simulations of simplified model synapses whose morphological features have been extracted from hundreds of actual synaptic junctions reconstructed by three-dimensional electron microscopy. We have examined the effects that parameters such as synaptic size or density of AMPA receptors have on the number of receptors that open after release of a single synaptic vesicle. Our results indicate that the maximum number of receptors that will open after the release of a single synaptic vesicle may show a ten-fold variation in the whole population of synapses. When individual synapses are considered, there is also a stochastical variability that is maximal in small synapses with low numbers of receptors. The number of postsynaptic receptors and the size of the synaptic junction are the most influential parameters, while the packing density of receptors or the concentration of extrasynaptic transporters have little or no influence on the opening of AMPA receptors. PMID:26107874
Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration
Fernandes, Ana Clara; Uytterhoeven, Valerie; Kuenen, Sabine; Wang, Yu-Chun; Slabbaert, Jan R.; Swerts, Jef; Kasprowicz, Jaroslaw; Aerts, Stein
Synaptic demise and accumulation of dysfunctional proteins are thought of as common features in neurodegeneration. However, the mechanisms by which synaptic proteins turn over remain elusive. In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, and identify endosome-to-lysosome trafficking as a mechanism for degradation of synaptic vesicle-associated proteins. In fly sky mutants, synaptic vesicles traveled excessively to endosomes. Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average, suggesting that older proteins are more efficiently degraded. Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking, controlled by the homotypic fusion and vacuole protein sorting (HOPS) complex, rescued the neurotransmission and neurodegeneration defects in sky mutants. Consistently, synaptic vesicle proteins were older in HOPS complex mutants, and these mutants also showed reduced neurotransmission. Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans. PMID:25422373
Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration.
Fernandes, Ana Clara; Uytterhoeven, Valerie; Kuenen, Sabine; Wang, Yu-Chun; Slabbaert, Jan R; Swerts, Jef; Kasprowicz, Jaroslaw; Aerts, Stein; Verstreken, Patrik
Synaptic demise and accumulation of dysfunctional proteins are thought of as common features in neurodegeneration. However, the mechanisms by which synaptic proteins turn over remain elusive. In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, and identify endosome-to-lysosome trafficking as a mechanism for degradation of synaptic vesicle-associated proteins. In fly sky mutants, synaptic vesicles traveled excessively to endosomes. Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average, suggesting that older proteins are more efficiently degraded. Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking, controlled by the homotypic fusion and vacuole protein sorting (HOPS) complex, rescued the neurotransmission and neurodegeneration defects in sky mutants. Consistently, synaptic vesicle proteins were older in HOPS complex mutants, and these mutants also showed reduced neurotransmission. Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans. PMID:25422373
The Neurexin/N-Ethylmaleimide-sensitive Factor (NSF) Interaction Regulates Short Term Synaptic Depression.
Li, Tao; Tian, Yao; Li, Qian; Chen, Huiying; Lv, Huihui; Xie, Wei; Han, Junhai
Although Neurexins, which are cell adhesion molecules localized predominantly to the presynaptic terminals, are known to regulate synapse formation and synaptic transmission, their roles in the regulation of synaptic vesicle release during repetitive nerve stimulation are unknown. Here, we show that nrx mutant synapses exhibit rapid short term synaptic depression upon tetanic nerve stimulation. Moreover, we demonstrate that the intracellular region of NRX is essential for synaptic vesicle release upon tetanic nerve stimulation. Using a yeast two-hybrid screen, we find that the intracellular region of NRX interacts with N-ethylmaleimide-sensitive factor (NSF), an enzyme that mediates soluble NSF attachment protein receptor (SNARE) complex disassembly and plays an important role in synaptic vesicle release. We further map the binding sites of each molecule and demonstrate that the NRX/NSF interaction is critical for both the distribution of NSF at the presynaptic terminals and SNARE complex disassembly. Our results reveal a previously unknown role of NRX in the regulation of short term synaptic depression upon tetanic nerve stimulation and provide new mechanistic insights into the role of NRX in synaptic vesicle release. PMID:25953899
Coupled Activity-dependent Trafficking of Synaptic SK2 Channels and AMPA Receptors
Lin, Mike T.; Lujan, Rafael; Watanabe, Masahiko; Frerking, Matthew; Maylie, James; Adelman, John P.
Small conductance Ca2+ activated K+ type 2 (SK2) channels are expressed in the postsynaptic density of CA1 neurons where they are activated by synaptically evoked Ca2+ influx to limit the size of excitatory postsynaptic potentials (EPSPs) and spine Ca2+ transients. At Schaffer collateral synapses, the induction of long-term potentiation (LTP) increases the ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated contribution to synaptic transmission and decreases the synaptic SK2 channel contribution through activity- protein kinase A-dependent channel endocytosis. Using a combination of electrophysiology and immuno-electron microscopy (iEM) in mice, the relationship between the dynamics of spine SK2 channels and AMPARs was investigated. Unlike AMPARs, synaptic SK2 channels under basal conditions do not rapidly recycle. Furthermore SK2 channels occupy a distinct population of endosomes separate from AMPARs. However, blocking vesicular exocytosis or blocking the delivery of synaptic GluA1-containing AMPARs during the induction of LTP block SK2 channel endocytosis. By ~2 hours after the induction of LTP, synaptic SK2 channel expression and function are restored. Thus, LTP-dependent endocytosis of SK2 is coupled to LTP-dependent AMPA exocoytosis, and the ~2 hour window after the induction of LTP during which synaptic SK2 activity is absent may be important for consolidating the later phases of LTP. PMID:20810893
Control of Synaptic Strength by Glial TNFalpha
Eric C. Beattie; David Stellwagen; Wade Morishita; Jacqueline C. Bresnahan; Byeong Keun Ha; Mark Von Zastrow; Michael S. Beattie; Robert C. Malenka
Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the
The Interplay between Synaptic Activity and Neuroligin Function in the CNS
Hu, Xiaoge; Luo, Jian-hong
Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previous in vitro and in vivo studies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other. PMID:25839034
Modulating mechanosensory afferent excitability by an atypical mGluR.
Watson, Sonia
Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles (SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor (mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for 'click-chemistry', an established technique for relatively quick, cheap, stereospecific and high-yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch-evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1??m (n?=?8; P?0.001). The addition of either a biotin or a fluorescein side group to ZCZ90, using the click-chemistry technique, did not affect the potency and hence these compounds will be used in further studies of the receptor. As well as the development of these compounds, the study found not only many similarities, but also some key differences between the two types of primary mechanosensory endings investigated. These differences must be taken into account in further study. However, they also present an intriguing opportunity for these receptors to be targeted selectively to modulate ending sensitivity as treatments for muscle spasm in multiple sclerosis and spinal cord injury, and possibly even baroreceptor firing to treat hypertension. PMID:26053109
Diverse in- and output polarities and high complexity of local synaptic and non-synaptic signaling within a chemically defined class of peptidergic Drosophila neurons
Karsai, Gergely; Pollák, Edit; Wacker, Matthias; Vömel, Matthias; Selcho, Mareike; Berta, Gergely; Nachman, Ronald J.; Isaac, R. Elwyn; Molnár, László; Wegener, Christian
Peptidergic neurons are not easily integrated into current connectomics concepts, since their peptide messages can be distributed via non-synaptic paracrine signaling or volume transmission. Moreover, the polarity of peptidergic interneurons in terms of in- and out-put sites can be hard to predict and is very little explored. We describe in detail the morphology and the subcellular distribution of fluorescent vesicle/dendrite markers in CCAP neurons (NCCAP), a well defined set of peptidergic neurons in the Drosophila larva. NCCAP can be divided into five morphologically distinct subsets. In contrast to other subsets, serial homologous interneurons in the ventral ganglion show a mixed localization of in- and output markers along ventral neurites that defy a classification as dendritic or axonal compartments. Ultrastructurally, these neurites contain both pre- and postsynaptic sites preferably at varicosities. A significant portion of the synaptic events are due to reciprocal synapses. Peptides are mostly non-synaptically or parasynaptically released, and dense-core vesicles and synaptic vesicle pools are typically well separated. The responsiveness of the NCCAP to ecdysis-triggering hormone may be at least partly dependent on a tonic synaptic inhibition, and is independent of ecdysteroids. Our results reveal a remarkable variety and complexity of local synaptic circuitry within a chemically defined set of peptidergic neurons. Synaptic transmitter signaling as well as peptidergic paracrine signaling and volume transmission from varicosities can be main signaling modes of peptidergic interneurons depending on the subcellular region. The possibility of region-specific variable signaling modes should be taken into account in connectomic studies that aim to dissect the circuitry underlying insect behavior and physiology, in which peptidergic neurons act as important regulators. PMID:23914156
High Bandwidth Synaptic Communication and Frequency Tracking in Human Neocortex
Testa-Silva, Guilherme; Verhoog, Matthijs B.; Linaro, Daniele; de Kock, Christiaan P. J.; Baayen, Johannes C.; Meredith, Rhiannon M.; De Zeeuw, Chris I.; Giugliano, Michele; Mansvelder, Huibert D.
Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits. PMID:25422947
Super-resolution microscopy of the synaptic active zone
Ehmann, Nadine; Sauer, Markus; Kittel, Robert J.
Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ) a variety of specialized proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modeling approaches has provided predictions of channel properties, numbers and even positions on the nanometer scale. However, elucidating the nanoscopic organization of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy (SRM) techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how SRM can be used to obtain information on the organization of AZ proteins. PMID:25688186
ERK, synaptic plasticity and acid-induced muscle pain.
Min, Ming-Yuan; Yang, Hsiu-Wen; Yen, Chen-Tung; Chen, Chien-Chang; Chen, Chih-Cheng; Cheng, Sin-Jhong
Chronic pain is characterized by post-injury pain hypersensitivity. Current evidence suggests that it might result from altered neuronal excitability and/or synaptic functions in pain-related pathways and brain areas, an effect known as central sensitization. Increased activity of extracellular signal-regulated kinase (ERK) has been well-demonstrated in the dorsal horn of the spinal cord in chronic pain animal models. Recently, increased ERK activity has also been identified in two supraspinal areas, the central amygdala and the paraventricular thalamic nucleus anterior. Our recent work on the capsular central amygdala has shown that this increased ERK activity can enhance synaptic transmission, which might account for central sensitization and behavior hypersensitivity in animals receiving noxious stimuli. PMID:21966555
Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat
Background The visceral afferents from various cervico-abdominal sensory receptors project to the dorsal vagal complex (DVC), which is composed of the nucleus of the solitary tract (NTS), the area postrema and the dorsal motor nucleus of the vagus nerve (DMX), via the vagus and glossopharyngeal nerves and then the solitary tract (TS) in the brainstem. While the excitatory transmission at the TS-NTS synapses shows strong frequency-dependent suppression in response to repeated stimulation of the afferents, the frequency dependence and short-term plasticity at the TS-DMX synapses, which also transmit monosynaptic information from the visceral afferents to the DVC neurons, remain largely unknown. Results Recording of the EPSCs activated by paired or repeated TS stimulation in the brainstem slices of rats revealed that, unlike NTS neurons whose paired-pulse ratio (PPR) is consistently below 0.6, the distribution of the PPR of DMX neurons shows bimodal peaks that are composed of type I (PPR, 0.6-1.5; 53% of 120 neurons recorded) and type II (PPR, < 0.6; 47%) neurons. Some of the type I DMX neurons showed paired-pulse potentiation. The distinction of these two types depended on the presynaptic release probability and the projection target of the postsynaptic cells; the distinction was not dependent on the location or soma size of the cell, intensity or site of the stimulation, the latency, standard deviation of latency or the quantal size. Repeated stimulation at 20 Hz resulted in gradual and potent decreases in EPSC amplitude in the NTS and type II DMX neurons, whereas type I DMX neurons displayed only slight decreases, which indicates that the DMX neurons of this type could be continuously activated by repeated firing of primary afferent fibers at a high (~10 Hz) frequency. Conclusions These two general types of short-term plasticity might contribute to the differential activation of distinct vago-vagal reflex circuits, depending on the firing frequency and type of visceral afferents. PMID:20961403
Moderate Alcohol Exposure during the Rat Equivalent to the Third Trimester of Human Pregnancy Alters Regulation of GABAA Receptor-Mediated Synaptic Transmission by Dopamine in the Basolateral Amygdala
Diaz, Marvin Rafael; Jotty, Karick; Locke, Jason L.; Jones, Sara R.; Valenzuela, Carlos Fernando
Fetal ethanol (EtOH) exposure leads to a range of neurobehavioral alterations, including deficits in emotional processing. The basolateral amygdala (BLA) plays a critical role in modulating emotional processing, in part, via dopamine (DA) regulation of GABA transmission. This BLA modulatory system is acquired during the first 2?weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) and we hypothesized that it could be altered by EtOH exposure during this period. We found that exposure of rats to moderate levels of EtOH vapor during the third trimester-equivalent [postnatal days (P) 2–12] alters DA modulation of GABAergic transmission in BLA pyramidal neurons during periadolescence. Specifically, D1R-mediated potentiation of spontaneous inhibitory postsynaptic currents (IPSCs) was significantly attenuated in EtOH-exposed animals. However, this was associated with a compensatory decrease in D3R-mediated suppression of miniature IPSCs. Western blot analysis revealed that these effects were not a result of altered D1R or D3R levels. BLA samples from EtOH-exposed animals also had significantly lower levels of the DA precursor (L-3,4-dihydroxyphenylalanine) but DA levels were not affected. This is likely a consequence of reduced catabolism of DA, as indicated by reduced levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the BLA samples. Anxiety-like behavior was not altered in EtOH-exposed animals. This is the first study to demonstrate that the modulatory actions of DA in the BLA are altered by developmental EtOH exposure. Although compensatory adaptations were engaged in our moderate EtOH exposure paradigm, it is possible that these are not able to restore homeostasis and correct anxiety-like behaviors under conditions of heavier EtOH exposure. Therefore, future studies should investigate the potential role of alterations in the modulatory actions of DA in the pathophysiology of fetal alcohol spectrum disorders. PMID:24904907
Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function.
Etherton, Mark; Földy, Csaba; Sharma, Manu; Tabuchi, Katsuhiko; Liu, Xinran; Shamloo, Mehrdad; Malenka, Robert C; Südhof, Thomas C
Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ?1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner. PMID:21808020
Vestibular afferent responses to linear accelerations in the alert squirrel monkey
NASA Technical Reports Server (NTRS)
Somps, Christopher J.; Schor, Robert H.; Tomko, David L.
The spontaneous activity of 40 otolith afferents and 44 canal afferents was recorded in 4 alert, intact squirrel monkeys. Polarization vectors and response properties of otolith afferents were determined during static re-orientations relative to gravity and during Earth-horizontal, sinusoidal, linear oscillations. Canal afferents were tested for sensitivity to linear accelerations. For regular otolith afferents, a significant correlation between upright discharge rate and sensitivity to dynamic acceleration in the horizontal plane was observed. This correlation was not present in irregular units. The sensitivity of otolith afferents to both static tilts and dynamic linear acceleration was much greater in irregularly discharging units than in regularly discharging units. The spontaneous activity and static and dynamic response properties of regularly discharging otolith afferents were similar to those reported in barbiturate-anesthetized squirrel monkeys. Irregular afferents also had similar dynamic response properties when compared to anesthetized monkeys. However, this sample of irregular afferents in alert animals had higher resting discharge rates and greater sensitivity to static tilts. The majority of otolith polarization vectors were oriented near the horizontal in the plane of the utricular maculae; however, directions of maximum sensitivity were different during dynamic and static testing. Canal afferents were not sensitive to static tilts or linear oscillations of the head.
Endogenous calcium buffering at photoreceptor synaptic terminals in salamander retina.
Van Hook, Matthew J; Thoreson, Wallace B
Calcium operates by several mechanisms to regulate glutamate release at rod and cone synaptic terminals. In addition to serving as the exocytotic trigger, Ca2+ accelerates replenishment of vesicles in cones and triggers Ca2+-induced Ca2+ release (CICR) in rods. Ca2+ thereby amplifies sustained exocytosis, enabling photoreceptor synapses to encode constant and changing light. A complete picture of the role of Ca2+ in regulating synaptic transmission requires an understanding of the endogenous Ca2+ handling mechanisms at the synapse. We therefore used the "added buffer" approach to measure the endogenous Ca2+ binding ratio (?endo ) and extrusion rate constant (?) in synaptic terminals of photoreceptors in retinal slices from tiger salamander. We found that ?endo was similar in both cell types-?25 and 50 in rods and cones, respectively. Using measurements of the decay time constants of Ca2+ transients, we found that ? was also similar, with values of ?100 s(-1) and 160 s(-1) in rods and cones, respectively. The measurements of ?endo differ considerably from measurements in retinal bipolar cells, another ribbon-bearing class of retinal neurons, but are comparable to similar measurements at other conventional synapses. The values of ? are slower than at other synapses, suggesting that Ca2+ ions linger longer in photoreceptor terminals, supporting sustained exocytosis, CICR, and Ca2+ -dependent ribbon replenishment. The mechanisms of endogenous Ca2+ handling in photoreceptors are thus well-suited for supporting tonic neurotransmission. Similarities between rod and cone Ca2+ handling suggest that neither buffering nor extrusion underlie differences in synaptic transmission kinetics. PMID:25049035
Microsecond-scale timing precision in rodent trigeminal primary afferents.
Bale, Michael R; Campagner, Dario; Erskine, Andrew; Petersen, Rasmus S
Communication in the nervous system occurs by spikes: the timing precision with which spikes are fired is a fundamental limit on neural information processing. In sensory systems, spike-timing precision is constrained by first-order neurons. We found that spike-timing precision of trigeminal primary afferents in rats and mice is limited both by stimulus speed and by electrophysiological sampling rate. High-speed video of behaving mice revealed whisker velocities of at least 17,000°/s, so we delivered an ultrafast "ping" (>50,000°/s) to single whiskers and sampled primary afferent activity at 500 kHz. Median spike jitter was 17.4 ?s; 29% of neurons had spike jitter < 10 ?s. These results indicate that the input stage of the trigeminal pathway has extraordinary spike-timing precision and very high potential information capacity. This timing precision ranks among the highest in biology. PMID:25878266
Microsecond-Scale Timing Precision in Rodent Trigeminal Primary Afferents
Bale, Michael R.; Campagner, Dario; Erskine, Andrew
Communication in the nervous system occurs by spikes: the timing precision with which spikes are fired is a fundamental limit on neural information processing. In sensory systems, spike-timing precision is constrained by first-order neurons. We found that spike-timing precision of trigeminal primary afferents in rats and mice is limited both by stimulus speed and by electrophysiological sampling rate. High-speed video of behaving mice revealed whisker velocities of at least 17,000°/s, so we delivered an ultrafast "ping" (>50,000°/s) to single whiskers and sampled primary afferent activity at 500 kHz. Median spike jitter was 17.4 ?s; 29% of neurons had spike jitter < 10 ?s. These results indicate that the input stage of the trigeminal pathway has extraordinary spike-timing precision and very high potential information capacity. This timing precision ranks among the highest in biology. PMID:25878266
Facilitative interactions between vasoactive intestinal polypeptide and receptor type-selective opioids: implications for sensory afferent regulation of spinal opioid action.
Liu, Nai Jiang; Gintzler, Alan R
Afferent tone is known to influence spinal opioid antinociception but the underlying neurochemical events are not well defined. This study investigates the consequence on cAMP formation of the coincident activation of signal transduction sequelae initiated by an afferent transmitter and opioid using dissociated spinal cord tissue. Afferent transmission was simulated via the addition of vasoactive intestinal polypeptide (VIP), a pelvic visceral afferent transmitter. Individually, mu, delta-, or kappa-selective opioids (1 microM each) did not alter basal spinal content of cAMP. However, VIP (1 microM) and the delta-opioid selective agonist, [D-Pen(2,5)] enkephalin (DPDPE; 1 microM), in combination, manifest a striking facilitative interaction to augment spinal levels of cAMP. Facilitative interactions between VIP and kappa- or mu-opioids were of a reduced magnitude or not observed, respectively. Blockade of delta-opioid or VIP receptors using naltrindole or VIP6-28, respectively antagonized the VIP-DPDPE facilitative interaction, as did pertussis toxin treatment. The VIP-DPDPE facilitative interaction was also eliminated by phospholipase Cbeta inhibition and inositol trisphosphate receptor blockade. This suggests that modulation of Ca(2+) trafficking by VIP and delta-opioid agonists is a point of convergence of their respective signal transduction cascades, the concomitant action at which achieves cytosolic Ca(2+) concentrations that are now sufficient for the activation of signaling molecules, e.g. Ca(2+)/calmodulin-stimulated adenylyl cyclase isoforms. These data underscore the plasticity of spinal delta-opioid neurochemical sequelae and their dependence on concomitant afferent transmitter-initiated neurochemical events. PMID:12480163
Afferent projections to the deep mesencephalic nucleus in the rat
Veazey, R.B.; Severin, C.M.
Afferent projections to the deep mesencephalic nucleus (DMN) of the rat were demonstrated with axonal transport techniques. Potential sources for projections to the DMN were first identified by injecting the nucleus with HRP and examining the cervical spinal cord, brain stem, and cortex for retrogradely labeled neurons. Areas consistently labeled were then injected with a tritiated radioisotope, the tissue processed for autoradiography, and the DMN examined for anterograde labeling. Afferent projections to the medial and/or lateral parts of the DMN were found to originate from a number of spinal, bulbar, and cortical centers. Rostral brain centers projecting to both medial and lateral parts of the DMN include the ipsilateral motor and somatosensory cortex, the entopeduncular nucleus, and zona incerta. at the level of the midbrain, the ipsilateral substantia nigra and contralateral DMN likewise project to the DMN. Furthermore, the ipsilateral superior colliculus projects to the DMN, involving mainly the lateral part of the nucleus. Afferents from caudal centers include bilateral projections from the sensory nucleus of the trigeminal complex and the nucleus medulla oblongata centralis, as well as from the contralateral dentate nucleus. The projections from the trigeminal complex and nucleus medullae oblongatae centralis terminate in the intermediate and medial parts of the DMN, whereas projections from the contralateral dentate nucleus terminate mainly in its lateral part. In general, the afferent connections of the DMN arise from diverse areas of the brain. Although most of these projections distribute throughout the entire extent of the DMN, some of them project mainly to either medial or lateral parts of the nucleus, thus suggesting that the organization of the DMN is comparable, at least in part, to that of the reticular formation of the pons and medulla, a region in which hodological differences between medial and lateral subdivisions are known to exist.
Click-evoked responses in vestibular afferents in rats.
Zhu, Hong; Tang, Xuehui; Wei, Wei; Mustain, William; Xu, Youguo; Zhou, Wu
Sound activates not only the cochlea but also the vestibular end organs. Research on this phenomenon led to the discovery of the sound-evoked vestibular myogenic potentials recorded from the sternocleidomastoid muscles (cervical VEMP, or cVEMP). Since the cVEMP offers simplicity and the ability to stimulate each labyrinth separately, its values as a test of human vestibular function are widely recognized. Currently, the cVEMP is interpreted as a test of saccule function based on the assumption that clicks primarily activate the saccule. However, sound activation of vestibular end organs other than the saccule has been reported. To provide the neural basis for interpreting clinical VEMP testing, we employed the broadband clicks used in clinical VEMP testing to examine the sound-evoked responses in a large sample of vestibular afferents in Sprague-Dawley rats. Recordings were made from 924 vestibular afferents from 106 rats: 255 from the anterior canal (AC), 202 from the horizontal canal (HC), 177 from the posterior canal (PC), 207 from the superior vestibular nerve otolith (SO), and 83 from the inferior nerve otolith (IO). Sound sensitivity of each afferent was quantified by computing the cumulative probability of evoking a spike (CPE). We found that clicks activated irregular afferents (normalized coefficient of variation of interspike intervals >0.2) from both the otoliths (81%) and the canals (43%). The order of end organ sound sensitivity was SO = IO > AC > HC > PC. Since the sternocleidomastoid motoneurons receive inputs from both the otoliths and the canals, these results provide evidence of a possible contribution from both of them to the click-evoked cVEMP. PMID:21613592
Peripheral nerve injury triggers central sprouting of myelinated afferents
Clifford J. Woolf; Peter Shortland; Richard E. Coggeshall
THE central terminals of primary afferent neurons are topographically highly ordered in the spinal cord1. Peripheral receptor sensitivity is reflected by dorsal horn laminar location: low-threshold mechanoreceptors terminate in laminae III and IV (refs 2, 3) and high-threshold nociceptors in laminae I, II and V (refs 4, 5). Unmyelinated C fibres, most of which are nociceptors6, terminate predominantly in lamina
Afferent diversity and the organization of central vestibular pathways
Jay M. Goldberg
This review considers whether the vestibular system includes separate populations of sensory axons innervating individual\\u000a organs and giving rise to distinct central pathways. There is a variability in the discharge properties of afferents supplying\\u000a each organ. Discharge regularity provides a marker for this diversity since fibers which differ in this way also differ in\\u000a many other properties. Postspike recovery of
Endothelin-1 induced desensitization in primary afferent neurons.
Smith, Terika P; Smith, Sherika N; Sweitzer, Sarah M
Endothelin-1 (ET-1) is a known algogen that causes acute pain and sensitization in humans and spontaneous nociceptive behaviors when injected into the periphery in rats, and is elevated during vaso-occlusive episodes (VOEs) in sickle cell disease (SCD) patients. Previously, our lab has shown that a priming dose of ET-1 produces sensitization to capsaicin-induce secondary hyperalgesia. The goal of this study was to determine if the sensitization induced by ET-1 priming is occurring at the level of the primary afferent neuron. Calcium imaging in cultured dorsal root ganglion (DRG) neurons was utilized to examine the effects of ET-1 on primary afferent neurons. ET-1 induces [Ca(2+)]i transients in unprimed cells. ET-1 induced [Ca(2+)]i transients are attenuated by priming with ET-1. This priming effect occurs whether the priming dose is given 0-4 days prior to the challenge dose. Similarly, ET-1 priming decreases capsaicin-induced [Ca(2+)]i transients. At the level of the primary afferent neuron, ET-1 priming has a desensitizing effect on challenge exposures to ET-1 and capsaicin. PMID:25220703
DEC-205 expression on migrating dendritic cells in afferent lymph.
Gliddon, Daniel R; Hope, Jayne C; Brooke, Gareth P; Howard, Christopher J
Previous studies have identified a 210 000-molecular weight molecule expressed at a high level on the surface of dendritic cells (DCs) in afferent lymph of cattle and evident on cells with the morphology of DCs in lymphoid tissues. Expression is either absent from other immune cells or is present at a lower level. The molecular weight and cellular distribution suggested that the molecule, called bovine WC6 antigen (workshop cluster), might be an orthologue of human DEC-205 (CD205). To establish whether this was the case, the open reading frame of bovine DEC-205 was amplified, by polymerase chain reaction, from thymic cDNA (accession no. AY264845). The cDNA sequence of bovine DEC-205 had 86% and 78% nucleic acid identity with human and mouse molecules, respectively. COS-7 cells transfected with a plasmid containing the cattle DEC-205 coding region expressed a molecule that stained with WC6-specific monoclonal antibody, showing that ruminant WC6 is an orthologue of DEC-205. Two-colour flow cytometry of mononuclear cells from afferent lymph draining cattle skin, and from blood, confirmed the high level of expression on large cells in lymph that were uniformly DC-LAMP positive and major histocompatibility complex class II positive. Within this DEC-205+ DC-LAMP+ population were subpopulations of cells that expressed the mannose receptor or SIRPalpha. The observations imply that DCs in afferent lymph are all DEC-205high, but not a uniform population of homogeneous mature DCs. PMID:15009426
Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology.
Creed, Meaghan; Pascoli, Vincent Jean; Lüscher, Christian
Circuit remodeling driven by pathological forms of synaptic plasticity underlies several psychiatric diseases, including addiction. Deep brain stimulation (DBS) has been applied to treat a number of neurological and psychiatric conditions, although its effects are transient and mediated by largely unknown mechanisms. Recently, optogenetic protocols that restore normal transmission at identified synapses in mice have provided proof of the idea that cocaine-adaptive behavior can be reversed in vivo. The most efficient protocol relies on the activation of metabotropic glutamate receptors, mGluRs, which depotentiates excitatory synaptic inputs onto dopamine D1 receptor medium-sized spiny neurons and normalizes drug-adaptive behavior. We discovered that acute low-frequency DBS, refined by selective blockade of dopamine D1 receptors, mimics optogenetic mGluR-dependent normalization of synaptic transmission. Consequently, there was a long-lasting abolishment of behavioral sensitization. PMID:25657248
Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity.
Brassai, A; Suvanjeiev, R-G; Bán, E-Gy; Lakatos, M
In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways. PMID:25540918
Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons.
Hanson, Jesse E; Deng, Lunbin; Hackos, David H; Lo, Shih-Ching; Lauffer, Benjamin E; Steiner, Pascal; Zhou, Qiang
Histone deacetylase 2 (HDAC2) negatively regulates excitatory synapse number and memory performance. However, whether HDAC2 regulation of excitatory synapses occurs in a cell-autonomous manner and whether HDAC2 regulates inhibitory synaptic functions are not well understood. To examine these aspects of HDAC2 function, we used sparse transfection of rat hippocampal slice cultures and whole-cell recordings in pyramidal neurons. HDAC2 knockdown (KD) in single postsynaptic pyramidal neurons enhanced, whereas HDAC2 overexpression (OE) reduced, excitatory synaptic transmission. Postsynaptic KD of HDAC2 also facilitated expression of long-term potentiation induced by subthreshold induction stimuli, without altering long-term depression. In contrast, HDAC2 KD reduced, whereas HDAC2 OE enhanced, inhibitory synaptic transmission. Alterations of postsynaptic GABA(A) receptors (GABA(A)Rs) likely underlie the impact of HDAC2 on inhibitory transmission. Consistent with this, we observed reduced transcript and protein levels of the GABA(A)R ?2 subunit and reduced surface expression of the ?2 subunit after HDAC2 KD. Furthermore, we observed a reduction in synaptic but not tonic GABA(A)R currents by HDAC2 KD, suggesting that HDAC2 selectively affects synaptic abundance of functional GABA(A)Rs. Immunostaining for postsynaptic GABA(A)Rs confirmed that HDAC2 KD and OE can regulate the synaptic abundance of these receptors. Together, these results highlight a role for HDAC2 in suppressing synaptic excitation and enhancing synaptic inhibition of hippocampal neurons. Therefore, a shift in the balance of synaptic excitation versus inhibition favoring excitation could contribute to the beneficial effects of reducing HDAC2 function in wild-type mice or of inhibiting HDACs in models of cognitive impairment. PMID:23554474
Transient receptor potential vanilloid 1-immunopositive neurons in the mouse are more prevalent within colon afferents compared to skin and muscle afferents.
Christianson, J A; McIlwrath, S L; Koerber, H R; Davis, B M
Previous studies in our laboratories found that isolectin B(4)(IB(4))-positive polymodal nociceptors in the mouse do not express transient receptor potential vanilloid 1 (TRPV1), nor does deletion of TRPV1 compromise the ability of these afferents to detect thermal stimuli. Considering that IB(4)-positive afferents account for over 70% of cutaneous nociceptors and that 30-50% of all mouse primary afferents express TRPV1, it is highly likely that many TRPV1-positive fibers project to non-cutaneous structures. To investigate this issue, Alexa Fluor-conjugated wheat germ agglutinin (WGA) or IB(4) was injected into the nerves innervating quadriceps muscle (femoral) or hindlimb skin (saphenous) of male C57Bl/6 mice. Similarly, Alexa Fluor-conjugated cholera toxin-beta was injected subserosally into the distal colon. Spinal ganglia at the appropriate level (L2-3 for saphenous and femoral nerves; L6 for colon) were processed for TRPV1, calcitonin gene-related peptide (CGRP), neurofilament heavy chain (NHF) and IB(4) visualization and examined on a confocal microscope. Colon afferents contained the highest percentage of both TRPV1- and CGRP-positive neurons, followed by femoral (WGA) and saphenous afferents (WGA and IB(4)). In contrast, NHF staining was more prevalent among femoral afferents, followed by saphenous (WGA) and colon afferents. IB(4) binding was observed in very few colon or saphenous (WGA) afferents, with no femoral afferents binding or transporting IB(4). Considering that the largest percentages of TRPV1-positive neurons observed in this study were within visceral and muscle afferent populations (neurons that typically are not subject to noxious temperatures), these results suggest that TRPV1 may not function primarily as a temperature sensor but rather as a detector of protons, vanilloid compounds or through interactions with other membrane proteins. PMID:16564640
Effect of hypergravity on the development of vestibulocerebellar afferent fibers
NASA Astrophysics Data System (ADS)
Bruce, L. L.
Gravity is a critical factor in the normal development of the vestibular system, as prolonged prenatal exposures to either micro- or hypergravity will alter the pattern of projections from specific vestibular organs to specific targets in the vestibular nuclei. This study addresses the effect of gravity on the development of vestibulocerebellar projections. In adult rats the semicircular canal afferents project mainly to the cerebellar nodulus whereas the otolith maculae project mainly to the ventral uvula of the cerebellum. To determine if the distribution pattern of these afferents is altered by exposures to altered gravity, 10 pregnant rats were exposed to hypergravity (1.5g) from embryonic day 12 (before vestibular ganglion neurons contact vestibular nuclei) to embryonic day 21 (near the time when the vestibular system becomes functional). Controls were exposed to Earth's gravity but otherwise received the same treatment. At the end of the exposure the embryos were deeply anesthetized and fixed by transcardiac perfusion with 4% paraformaldehyde in 0.1 M phosphate buffer (pH7.4). Filter strips coated with DiI and PTIR were implanted into the saccule (gravistatic vestibular receptor) or into the posterior vertical canal (angular acceleration receptor), and allowed to diffuse for 2 weeks at 37°C. Then the brains were dissected and sectioned for fluorescent confocal imaging. Examination of the control cerebella revealed that the canal and otolith afferents have reached the nodulus and uvula, and axons extend into the internal granular, Purkinje, and molecular layers. Projections from the saccule and posterior vertical canal were partially segregated into their respective domains, the uvula and nodulus. In contrast, in hypergravity-exposed rat fetuses the saccule and posterior vertical canal projections were poorly segregated, and both organs contributed labeled fibers to all layers of the nodulus and uvula. This contrasts with the increased afferent segregation patterns observed in the vestibular nuclei after hypergravity exposures. Together these results suggest that hypergravity exposure delays the development of afferent segregation in the cerebellum, and furthermore that each vestibular target responds differently to the influence of gravity. Supported by NASA grant NAG2-1353.
Network effects of synaptic modifications.
Liljenström, H
In this paper, we use computational models of varying complexity to investigate the role of synaptic modifications for cortical network properties. In particular, we study how the dynamics can be regulated by neuromodulators, intrinsic noise and chemical agents. We focus on the complex neurodynamics and its modulation, and how this is related to the neural circuitry, where connectivity enhancement and pruning is considered. The emphasis is on the overall network structures, with feedforward and feedback loops between excitatory and inhibitory neurons at several layers and distances, and less details at the synaptic level. Our models aim at linking processes at a molecular and cellular (microscale), with processes at a network level (mesoscale), which in turn are linked to the mental processes and cognitive functions (macroscale). We also discuss the relevance of these results for clinical and experimental neuroscience, with applications to learning, memory, arousal, and mental disorders. PMID:20486052
Bistable Switches for Synaptic Plasticity
NSDL National Science Digital Library
Hideaki Ogasawara (Kyoto; National Institute of Information and Communications Technology REV)
A persistent decrease in synaptic efficacy, called long-term depression (LTD), of the parallel fiber–Purkinje cell synapse is thought to underlie some forms of learning and memory in the cerebellum. Simulation studies predicted that mitogen-activated protein kinase and protein kinase C would mutually activate each other and make a bistable positive feedback loop, thereby providing a molecular basis for LTD. This claim stimulated experimenters to successfully demonstrate the feedback loop and its pivotal role in cerebellar LTD.
Synaptic plasticity and sensory-motor improvement following fibrin sealant dorsal root reimplantation and mononuclear cell therapy
Benitez, Suzana U.; Barbizan, Roberta; Spejo, Aline B.; Ferreira, Rui S.; Barraviera, Benedito; Góes, Alfredo M.; de Oliveira, Alexandre L. R.
Root lesions may affect both dorsal and ventral roots. However, due to the possibility of generating further inflammation and neuropathic pain, surgical procedures do not prioritize the repair of the afferent component. The loss of such sensorial input directly disturbs the spinal circuits thus affecting the functionality of the injuried limb. The present study evaluated the motor and sensory improvement following dorsal root reimplantation with fibrin sealant (FS) plus bone marrow mononuclear cells (MC) after dorsal rhizotomy. MC were used to enhance the repair process. We also analyzed changes in the glial response and synaptic circuits within the spinal cord. Female Lewis rats (6–8 weeks old) were divided in three groups: rhizotomy (RZ group), rhizotomy repaired with FS (RZ+FS group) and rhizotomy repaired with FS and MC (RZ+FS+MC group). The behavioral tests electronic von-Frey and Walking track test were carried out. For immunohistochemistry we used markers to detect different synapse profiles as well as glial reaction. The behavioral results showed a significant decrease in sensory and motor function after lesion. The reimplantation decreased glial reaction and improved synaptic plasticity of afferent inputs. Cell therapy further enhanced the rewiring process. In addition, both reimplanted groups presented twice as much motor control compared to the non-treated group. In conclusion, the reimplantation with FS and MC is efficient and may be considered an approach to improve sensory-motor recovery following dorsal rhizotomy. PMID:25249946
Neurotoxic and Synaptic Effects of Okadaic Acid, an Inhibitor of Protein Phosphatases
Ricardo Tapia; Fernando Peiia; Clorinda Arias
Protein phosphorylation and dephosphorylation reactions, catalyzed by kinases and phosphatases, are involved in the regulation of a wide variety of physiological processes. In the nervous system, such reactions seem to modulate the function of several proteins crucial in synaptic transmission, including voltage-gated and ligand-gated channels, neurotransmitter release, and neurotransmitter transporters. On the other hand, hyperphosphorylation of certain cytoskeletal proteins or
Short-Term Synaptic Plasticity in the Visual Cortex During Development
Sur, Mriganka
, VA 23298-0709 and department of Brain and Cognitive Sciences, Massachusetts Institute of Technology-pulse depression, a decrease in the second excitatory response relative to the first, and a concomitant decrease revealed depression of synaptic transmission following an initial stimulus, while most of the other neurons
Synaptic transfer of dynamic motion information between identified neurons in the visual system of the blowfly
A.-K. Warzecha; R. Kurtz; M. Egelhaaf
Synaptic transmission is usually studied in vitro with electrical stimulation replacing the natural input of the system. In contrast, we analyzed in vivo transfer of visual motion information from graded-potential presynaptic to spiking postsynaptic neurons in the fly. Motion in the null direction leads to hyperpolarization of the presynaptic neuron but does not much influence the postsynaptic cell, because its
Abraham, Nader G.
, buffering intracellular free [Ca2 ] with BAPTA similarly prevented the effects on GABAA receptor-mediated synaptic transmission, suggest- ing intracellular Ca2 homeostasis is important to maintain GABAA receptor function. The findings further support a role for activation of L-type VGCCs, and perhaps other Ca2
Astroglial calcium signaling displays short-term plasticity and adjusts synaptic efficacy
Sibille, Jérémie; Zapata, Jonathan; Teillon, Jérémie; Rouach, Nathalie
Astrocytes are dynamic signaling brain elements able to sense neuronal inputs and to respond by complex calcium signals, which are thought to represent their excitability. Such signaling has been proposed to modulate, or not, neuronal activities ranging from basal synaptic transmission to epileptiform discharges. However, whether calcium signaling in astrocytes exhibits activity-dependent changes and acutely modulates short-term synaptic plasticity is currently unclear. We here show, using dual recordings of astroglial calcium signals and synaptic transmission, that calcium signaling in astrocytes displays, concomitantly to excitatory synapses, short-term plasticity in response to prolonged repetitive and tetanic stimulations of Schaffer collaterals. We also found that acute inhibition of calcium signaling in astrocytes by intracellular calcium chelation rapidly potentiates excitatory synaptic transmission and short-term plasticity of Shaffer collateral CA1 synapses, i.e., paired-pulse facilitation and responses to tetanic and prolonged repetitive stimulation. These data reveal that calcium signaling of astrocytes is plastic and down-regulates basal transmission and short-term plasticity of hippocampal CA1 glutamatergic synapses. PMID:26074766
Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices
Harris, Alexander Z; Pettit, Diana L
N-methyl-d-aspartate receptor (NMDAR) activation can trigger both long- and short-term plasticity, promote cell survival, and initiate cell death. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on whether synaptic or extrasynaptic receptors are activated. Here we have examined the spatial distribution of NMDARs of CA1 pyramidal neurons in acutely dissected hippocampal slices. Using a physiological definition of extrasynaptic receptors as those not accessible to single release events, we find that extrasynaptic NMDARs comprise a substantial proportion of the dendritic NMDAR pool (36%). This pool of extrasynaptic NMDARs is stable and does not shuttle into the synaptic receptor pool, as we observe no recovery of synaptic current after MK-801 synaptic blockade and washout. The subunit composition of synaptic and extrasynaptic NMDA receptor pools is similar at 3 weeks of age, with NR2B subunits present in both compartments. NR2B receptors are not enriched in the extrasynaptic compartment. Our data suggest that any role played by extrasynaptic NMDARs in synaptic transmission is dictated by their subcellular location rather than their subunit composition or mobility. PMID:17717018
Functional Neural Development from Human Embryonic Stem Cells: Accelerated Synaptic Activity via Astrocyte Coculture
Johnson, M. Austin; Weick, Jason P.; Pearce, Robert A.; Zhang, Su-Chun
How a naive human neuroepithelial cell becomes an electrophysiologically active neuron remains unknown. Here, we describe the early physiological development of neurons differentiating from naive human embryonic stem (hES) cells. We found that differentiating neuronal cells progressively decrease their resting membrane potential, gain characteristic Na+ and K+ currents, and fire mature action potentials by 7 weeks of differentiation. This is similar to the maturation pattern observed in animals, albeit on a greatly expanded time scale. An additional 3 weeks of differentiation resulted in neurons that could fire repetitive trains of action potentials in response to depolarizing current pulses. The onset of spontaneous synaptic activity also occurred after 7 weeks of differentiation, in association with the differentiation of astrocytes within the culture. Cocultures of hES cell-derived neuroepithelial cells with exogenous astrocytes significantly accelerated the onset of synaptic currents but did not alter action potential generation. These findings suggest that the development of membrane characteristics and action potentials depend on the intrinsic maturation of Na+ and K+ currents, whereas synaptic transmission is enhanced by astrocytes, which may be achieved independently of the maturation of action potentials. Furthermore, we found that although astrocyte-conditioned medium accelerated synaptic protein localization, it did not increase synaptic activity, suggesting a contact-dependant mechanism by which astrocytes augment synaptic activity. These results lay the foundation for future studies examining the functional development of human neurons and provide support for the potential application of human cells in restorative neuronal therapies. PMID:17376968
SIRT1 is essential for normal cognitive function and synaptic plasticity
Michán, Shaday; Li, Ying; Chou, Maggie Meng-Hsiu; Parrella, Edoardo; Ge, Huanying; Long, Jeffrey M.; Allard, Joanne S.; Lewis, Kaitlyn; Miller, Marshall; Xu, Wei; Mervis, Ronald F.; Chen, Jing; Guerin, Karen I.; Smith, Lois E. H.; McBurney, Michael W.; Sinclair, David A.; Baudry, Michel; de Cabo, Rafael; Longo, Valter D.
Conservation of normal cognitive functions relies on the proper performance of the nervous system at the cellular and molecular level. The mammalian NAD+-dependent deacetylase, SIRT1, impacts different processes potentially involved in the maintenance of brain integrity such as chromatin remodeling, DNA repair, cell survival and neurogenesis. Here we show that SIRT1 is expressed in neurons of the hippocampus, a key structure in learning and memory. Using a combination of behavioral and electrophysiological paradigms we analyzed the effects of SIRT1 deficiency and overexpression on mouse learning and memory as well as on synaptic plasticity. We demonstrated that the absence of SIRT1 impaired cognitive abilities, including immediate memory, classical conditioning and spatial learning. In addition, we found that the cognitive deficits in SIRT1 knockout mice were associated with defects in synaptic plasticity without alterations in basal synaptic transmission or NMDA receptor function. Brains of SIRT1-KO mice exhibited normal morphology and dendritic spine structure but display a decrease in dendritic branching, branch length and complexity of neuronal dendritic arbors. Also, a decrease in ERK1/2 phosphorylation and altered expression of hippocampal genes involved in synaptic function, lipid metabolism and myelination were detected in SIRT1-KO mice. In contrast, mice with high levels of SIRT1 expression in brain exhibited regular synaptic plasticity and memory. We conclude that SIRT1 is indispensable for normal learning, memory and synaptic plasticity in mice. PMID:20660252
Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats.
Sun, Miao-Kun; Xu, Hui; Alkon, Daniel L
Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function. PMID:11805198
Somato-sensory paths to the second cortical projection area of the group I muscle afferents
Landgren, S.; Silfvenius, H.; Wolsk, D.
1. Cats anaesthetized with chloralose and paralysed with Flaxedil were used. The projections of muscle, joint and skin afferents to the cortical fold hidden in the anterior suprasylvian sulcus were investigated with micro-electrode recording techniques. 2. Electrical stimulation of Group I muscle afferents from the contralateral forelimb evoked a negative focal potential (latency 5 msec) in a locus of 1-2 mm diameter found in the lower bank of the fold. In one experiment a response to Group I muscle afferents from the contralateral hind limb was observed. The Group I potentials disappeared after sectioning of the dorsal columns at C3. 3. Groups II and III muscle afferents, low threshold skin afferents and joint afferents also evoked potentials in the Group I locus. It was concluded that the joint afferents originated mainly in the Ruffini endings of the joint capsule. 4. Groups II and III muscle afferents, low threshold skin and low threshold joint afferents projected to the upper bank of the suprasylvian fold. A certain somatotopic arrangement was observed. 5. The possibility of connexions between the cortex of the anterior suprasylvian fold and the primary somato-sensory projection areas was discussed, as well as the organization of the loci in the fold in terms of cell colonies with different properties. PMID:4860991
Corneal afferents differentially target thalamic- and parabrachial-projecting neurons in spinal trigeminal nucleus caudalis.
Aicher, S A; Hermes, S M; Hegarty, D M
Dorsal horn neurons send ascending projections to both thalamic nuclei and parabrachial nuclei; these pathways are thought to be critical pathways for central processing of nociceptive information. Afferents from the corneal surface of the eye mediate nociception from this tissue which is susceptible to clinically important pain syndromes. This study examined corneal afferents to the trigeminal dorsal horn and compared inputs to thalamic- and parabrachial-projecting neurons. We used anterograde tracing with cholera toxin B subunit to identify corneal afferent projections to trigeminal dorsal horn, and the retrograde tracer FluoroGold to identify projection neurons. Studies were conducted in adult male Sprague-Dawley rats. Our analysis was conducted at two distinct levels of the trigeminal nucleus caudalis (Vc) which receive corneal afferent projections. We found that corneal afferents project more densely to the rostral pole of Vc than the caudal pole. We also quantified the number of thalamic- and parabrachial-projecting neurons in the regions of Vc that receive corneal afferents. Corneal afferent inputs to both groups of projection neurons were also more abundant in the rostral pole of Vc. Finally, by comparing the frequency of corneal afferent appositions to thalamic- versus parabrachial-projecting neurons, we found that corneal afferents preferentially target parabrachial-projecting neurons in trigeminal dorsal horn. These results suggest that nociceptive pain from the cornea may be primarily mediated by a non-thalamic ascending pathway. PMID:23201828
Developmental expression of inhibitory synaptic long-term potentiation in the lateral superior olive.
Kotak, Vibhakar C; Sanes, Dan H
Principal neurons of the lateral superior olivary nucleus (LSO) respond selectively to interaural level differences (ILD). To perform this computation, LSO neurons integrate excitatory synaptic drive from the ipsilateral ear with inhibitory synaptic drive from the contralateral ear via the medial nucleus of the trapezoid body (MNTB). Previous research demonstrated that inhibitory terminals from the MNTB to the LSO are eliminated during development. Furthermore, MNTB synapses display an activity- and age-dependent long-term depression (iLTD) that may contribute to inhibitory synapse elimination. However, inhibitory synapses that are stabilized become stronger. Here, we asked whether MNTB synapses displayed activity-dependent strengthening. Whole-cell recordings were obtained from LSO neurons in a gerbil brain slice before and after hearing onset. The inhibitory MNTB afferents were stimulated at a low rate, similar to spontaneous discharge rates observed in vivo. The MNTB-evoked inhibitory responses were strengthened by 40-300% when synaptic activity was coupled with postsynaptic membrane depolarization, exogenous glutamate application, or activation of ipsilateral excitatory synaptic inputs. This inhibitory long-term potentiation (iLTP) was associated with increased spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. One hour after iLTP induction, IPSCs could not be de-potentiated by the MNTB stimulation pattern that induces iLTD in control slices. iLTP could only be induced after hearing onset (>P12), and was blocked in the presence of a GABAB receptor antagonist. Together, these results suggest a developmental period during which the induction of iLTP depends on the conjoint activation of GABAB receptors and postsynaptic depolarization. We propose that iLTP may support stabilization of un-pruned MNTB connections and contribute to the emergence of ILD processing in the mature LSO. PMID:24994969
Developmental expression of inhibitory synaptic long-term potentiation in the lateral superior olive
Kotak, Vibhakar C.; Sanes, Dan H.
Principal neurons of the lateral superior olivary nucleus (LSO) respond selectively to interaural level differences (ILD). To perform this computation, LSO neurons integrate excitatory synaptic drive from the ipsilateral ear with inhibitory synaptic drive from the contralateral ear via the medial nucleus of the trapezoid body (MNTB). Previous research demonstrated that inhibitory terminals from the MNTB to the LSO are eliminated during development. Furthermore, MNTB synapses display an activity- and age-dependent long-term depression (iLTD) that may contribute to inhibitory synapse elimination. However, inhibitory synapses that are stabilized become stronger. Here, we asked whether MNTB synapses displayed activity-dependent strengthening. Whole-cell recordings were obtained from LSO neurons in a gerbil brain slice before and after hearing onset. The inhibitory MNTB afferents were stimulated at a low rate, similar to spontaneous discharge rates observed in vivo. The MNTB-evoked inhibitory responses were strengthened by 40–300% when synaptic activity was coupled with postsynaptic membrane depolarization, exogenous glutamate application, or activation of ipsilateral excitatory synaptic inputs. This inhibitory long-term potentiation (iLTP) was associated with increased spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. One hour after iLTP induction, IPSCs could not be de-potentiated by the MNTB stimulation pattern that induces iLTD in control slices. iLTP could only be induced after hearing onset (>P12), and was blocked in the presence of a GABAB receptor antagonist. Together, these results suggest a developmental period during which the induction of iLTP depends on the conjoint activation of GABAB receptors and postsynaptic depolarization. We propose that iLTP may support stabilization of un-pruned MNTB connections and contribute to the emergence of ILD processing in the mature LSO. PMID:24994969
Synaptic and Behavioral Profile of Multiple Glutamatergic Inputs to the Nucleus Accumbens
Britt, Jonathan P.; Benaliouad, Faiza; McDevitt, Ross A.; Stuber, Garret D.; Wise, Roy A.; Bonci, Antonello
SUMMARY Excitatory afferents to the nucleus accumbens (NAc) are thought to facilitate reward seeking by encoding reward-associated cues. Selective activation of different glutamatergic inputs to the NAc can produce divergent physiological and behavioral responses, but mechanistic explanations for these pathway-specific effects are lacking. Here, we compared the innervation patterns and synaptic properties of ventral hippocampus, basolateral amygdala, and prefrontal cortex input to the NAc. Ventral hippocampal input was found to be uniquely localized to the medial NAc shell, where it was predominant and selectively potentiated following cocaine exposure. In vivo, bidirectional optogenetic manipulations of this pathway attenuated and enhanced cocaine-induced locomotion. Challenging the idea that any of these inputs encode motivationally-neutral information, activation of each discrete pathway reinforced instrumental behaviors. Finally, direct optical activation of medium spiny neurons proved to be capable of supporting self-stimulation, demonstrating that behavioral reinforcement is an explicit consequence of strong excitatory drive to the NAc. PMID:23177963
Homeostatic Control of Synaptic Activity by Endogenous Adenosine is Mediated by Adenosine Kinase
Diógenes, Maria José; Neves-Tomé, Raquel; Fucile, Sergio; Martinello, Katiuscia; Scianni, Maria; Theofilas, Panos; Lopatá?, Jan; Ribeiro, Joaquim A.; Maggi, Laura; Frenguelli, Bruno G.; Limatola, Cristina; Boison, Detlev; Sebastiăo, Ana M.
Extracellular adenosine, a key regulator of neuronal excitability, is metabolized by astrocyte-based enzyme adenosine kinase (ADK). We hypothesized that ADK might be an upstream regulator of adenosine-based homeostatic brain functions by simultaneously affecting several downstream pathways. We therefore studied the relationship between ADK expression, levels of extracellular adenosine, synaptic transmission, intrinsic excitability, and brain-derived neurotrophic factor (BDNF)-dependent synaptic actions in transgenic mice underexpressing or overexpressing ADK. We demonstrate that ADK: 1) Critically influences the basal tone of adenosine, evaluated by microelectrode adenosine biosensors, and its release following stimulation; 2) determines the degree of tonic adenosine-dependent synaptic inhibition, which correlates with differential plasticity at hippocampal synapses with low release probability; 3) modulates the age-dependent effects of BDNF on hippocampal synaptic transmission, an action dependent upon co-activation of adenosine A2A receptors; and 4) influences GABAA receptor-mediated currents in CA3 pyramidal neurons. We conclude that ADK provides important upstream regulation of adenosine-based homeostatic function of the brain and that this mechanism is necessary and permissive to synaptic actions of adenosine acting on multiple pathways. These mechanistic studies support previous therapeutic studies and implicate ADK as a promising therapeutic target for upstream control of multiple neuronal signaling pathways crucial for a variety of neurological disorders. PMID:22997174
Synaptic rearrangement following axonal injury: Old and new players.
Spejo, Aline Barroso; Oliveira, Alexandre L R
Following axotomy, the contact between motoneurons and muscle fibers is disrupted, triggering a retrograde reaction at the neuron cell body within the spinal cord. Together with chromatolysis, a hallmark of such response to injury is the elimination of presynaptic terminals apposing to the soma and proximal dendrites of the injured neuron. Excitatory inputs are preferentially eliminated, leaving the cells under an inhibitory influence during the repair process. This is particularly important to avoid glutamate excitotoxicity. Such shift from transmission to a regeneration state is also reflected by deep metabolic changes, seen by the regulation of several genes related to cell survival and axonal growth. It is unclear, however, how exactly synaptic stripping occurs, but there is substantial evidence that glial cells play an active role in this process. In one hand, immune molecules, such as the major histocompatibility complex (MHC) class I, members of the complement family and Toll-like receptors are actively involved in the elimination/reapposition of presynaptic boutons. On the other hand, plastic changes that involve sprouting might be negatively regulated by extracellular matrix proteins such as Nogo-A, MAG and scar-related chondroitin sulfate proteoglycans. Also, neurotrophins, stem cells, physical exercise and several drugs seem to improve synaptic stability, leading to functional recovery after lesion. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID:25445484
Development of convergent synaptic inputs to subpopulations of autonomic neurons.
Anderson, Rebecca L; Jobling, Phillip; Matthew, Sue E; Gibbins, Ian L
Visceromotor neurons in mammalian prevertebral sympathetic ganglia receive convergent synaptic inputs from spinal preganglionic neurons and peripheral intestinofugal neurons projecting from the enteric plexuses. Vasomotor neurons in the same ganglia receive only preganglionic inputs. How this pathway-specific pattern of connectivity is established is unknown. We have used a combination of immunohistochemical, ultrastructural, and electrophysiological techniques to investigate the development of synaptic inputs onto visceromotor and vasomotor neurons in the celiac ganglion of guinea pigs. Functional synaptogenesis occurred primarily from early fetal (F30-F35) to midfetal (F36-F45) stages, after the neurochemical differentiation of vasomotor and visceromotor neurons but before establishment of their electrophysiological phenotypes. Intestinofugal inputs were detected only on presumptive visceromotor neurons located primarily in medial regions of the ganglion. The number of ultrastructurally identified synaptic profiles increased in parallel with functional synaptogenesis, especially in medial regions, where dendritic growth rates also were higher. However, the expression of immunoreactivity to choline acetyltransferase in the terminals of inputs was very low until late fetal stages, after functional transmission already had been established. These results show that peripheral intestinofugal neurons directly establish appropriate functional connections with their target visceromotor neurons simultaneously with the development of functional preganglionic inputs to both visceromotor and vasomotor neurons. It seems likely that synaptogenesis occurs independently of the neurochemical differentiation of the target neurons but is closely related to the pathway-specific dendritic development of those neurons. PMID:11984817
Endocannabinoid Signaling and Long-term Synaptic Plasticity
Heifets, Boris D.; Castillo, Pablo E.
Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the CNS. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g. cannabis) and endogenous cannabinoids affect behavior. As behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, while remarkably similar at various synapses, is controlled by an array of regulatory influences which we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity. PMID:19575681
Intergeniculate leaflet and ventral lateral geniculate nucleus afferent connections: An anatomical substrate for functional input from the vestibulo-visuomotor system.
Horowitz, Seth S; Blanchard, Jane H; Morin, Lawrence P
The intergeniculate leaflet (IGL) has widespread projections to the basal forebrain and visual midbrain, including the suprachiasmatic nucleus (SCN). Here we describe IGL-afferent connections with cells in the ventral midbrain and hindbrain. Cholera toxin B subunit (CTB) injected into the IGL retrogradely labels neurons in a set of brain nuclei most of which are known to influence visuomotor function. These include the retinorecipient medial, lateral and dorsal terminal nuclei, the nucleus of Darkschewitsch, the oculomotor central gray, the cuneiform, and the lateral dorsal, pedunculopontine, and subpeduncular pontine tegmental nuclei. Intraocular CTB labeled a retinal terminal field in the medial terminal nucleus that extends dorsally into the pararubral nucleus, a location also containing cells projecting to the IGL. Distinct clusters of IGL-afferent neurons are also located in the medial vestibular nucleus. Vestibular projections to the IGL were confirmed by using anterograde tracer injection into the medial vestibular nucleus. Other IGL-afferent neurons are evident in Barrington's nucleus, the dorsal raphe, locus coeruleus, and retrorubral nucleus. Injection of a retrograde, trans-synaptic, viral tracer into the SCN demonstrated transport to cells as far caudal as the vestibular system and, when combined with IGL injection of CTB, confirmed that some in the medial vestibular nucleus polysynaptically project to the SCN and monosynaptically to the IGL, as do cells in other brain regions. The results suggest that the IGL may be part of the circuitry governing visuomotor activity and further indicate that circadian rhythmicity might be influenced by head motion or visual stimuli that affect the vestibular system. PMID:15164424
?-Opioid receptor inhibition of substance P release from primary afferents disappears in neuropathic pain but not inflammatory pain.
Chen, W; McRoberts, J A; Marvizón, J C G
Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in ?-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. Noxious stimulation of the paw with CCI produced inconsistent NK1R internalization, suggesting that transmission of nociceptive signals by the injured nerve was variably impaired after CCI. This idea was supported by the fact that CCI produced only small changes in the ability of exogenous substance P to induce NK1R internalization or in the release of substance P evoked centrally from site of nerve injury. In subsequent experiments, NK1R internalization was induced in spinal cord slices by stimulating the dorsal root ipsilateral to CCI. We observed a complete loss of the inhibition of substance P release by the ?-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in CCI rats but not in sham-operated rats. In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund's adjuvant and in naďve rats. This loss of inhibition was not due to ?-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by ?-opioid receptors, probably by hindering their signaling mechanisms. PMID:24583035
The Phase Difference Between Neural Drives to Antagonist Muscles in Essential Tremor Is Associated with the Relative Strength of Supraspinal and Afferent Input.
Gallego, Juan A; Dideriksen, Jakob L; Holobar, Ales; Ibáńez, Jaime; Glaser, Vojko; Romero, Juan P; Benito-León, Julián; Pons, José L; Rocon, Eduardo; Farina, Dario
The pathophysiology of essential tremor (ET), the most common movement disorder, is not fully understood. We investigated which factors determine the variability in the phase difference between neural drives to antagonist muscles, a long-standing observation yet unexplained. We used a computational model to simulate the effects of different levels of voluntary and tremulous synaptic input to antagonistic motoneuron pools on the tremor. We compared these simulations to data from 11 human ET patients. In both analyses, the neural drive to muscle was represented as the pooled spike trains of several motor units, which provides an accurate representation of the common synaptic input to motoneurons. The simulations showed that, for each voluntary input level, the phase difference between neural drives to antagonist muscles is determined by the relative strength of the supraspinal tremor input to the motoneuron pools. In addition, when the supraspinal tremor input to one muscle was weak or absent, Ia afferents provided significant common tremor input due to passive stretch. The simulations predicted that without a voluntary drive (rest tremor) the neural drives would be more likely in phase, while a concurrent voluntary input (postural tremor) would lead more frequently to an out-of-phase pattern. The experimental results matched these predictions, showing a significant change in phase difference between postural and rest tremor. They also indicated that the common tremor input is always shared by the antagonistic motoneuron pools, in agreement with the simulations. Our results highlight that the interplay between supraspinal input and spinal afferents is relevant for tremor generation. PMID:26063924
Nonvolatile programmable neural network synaptic array
NASA Technical Reports Server (NTRS)
Tawel, Raoul (inventor)
A floating-gate metal oxide semiconductor (MOS) transistor is implemented for use as a nonvolatile analog storage element of a synaptic cell used to implement an array of processing synaptic cells. These cells are based on a four-quadrant analog multiplier requiring both X and Y differential inputs, where one Y input is UV programmable. These nonvolatile synaptic cells are disclosed fully connected in a 32 x 32 synaptic cell array using standard very large scale integration (VLSI) complementary MOS (CMOS) technology.
Preferentially regulated expression of connexin 43 in the developing spiral ganglion neurons and afferent terminals in post-natal rat cochlea.
Liu, W J; Yang, J
The expression pattern of connexin 43 (Cx43) in the cochlea is not determined and is controversial. Since the presence of Cx43 is essential for hearing, we re-examined its distribution during postnatal development of rat cochlea. Cx43 protein was expressed in spiral ganglion neurons (SGNs) and their neurite terminals innervating the inner and outer hair cells (IHCs and OHCs) as early as birth (post-natal day 0, P0), and persisted until P14. Double immuno?uorescence staining, using two antibodies against Cx43 and TUJ1, a marker for all SGNs and afferent terminals, showed that immunoreactivity for Cx43 and TUJ1 was perfectly colocalized in SGNs and afferent terminals associated with the IHCs and OHCs. However, beyond P14, Cx43 immunostaining could no longer be detected in the region of the synaptic terminals at the bases of IHCs and OHCs (P17, adult). In contrast, Cx43 maintained its expression in SGNs into adulthood. We further performed quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) to identify the presence of Cx43 mRNA in the modiolus (mainly containing SGNs). Cx43 mRNA was higher at P8, compared with P1, and subsequently decreased at P14. These results indicated that Cx43 correlated with cochlear synaptogenesis and establishment of auditory neurotransmission. PMID:25820563
The Chicken Suprachiasmatic Nuclei: I. Efferent and Afferent Connections
Cantwell, Elizabeth L.; Cassone, Vincent M.
The avian circadian system is composed of multiple inputs, oscillators and outputs. Among its oscillators are the pineal gland, retinae and a hypothalamic structure assumed to be homologous to the mammalian suprachiasmatic nucleus (SCN). Two structures have been suggested as this homolog—the medial SCN (mSCN) and the visual SCN (vSCN). The present study employed biotin dextran amine (BDA) and cholera toxin B subunit (CTB) as anterograde and retrograde tracers to investigate the connectivity of the mSCN and vSCN in order to address this issue. Intravitreal injections of CTB were used to determine whether one or both of these structures receives afferent input from retinal ganglion cells. Both the vSCN and mSCN receive terminal retinal input, with the strongest input terminating in the vSCN. Precise iontophoretic injections of BDA and CTB in the mSCN and vSCN were used to identify efferents and afferents. The avian mSCN and vSCN collectively express more efferents and afferents than does the mammalian SCN. A subset of these connections matches the connections that have been established in rodent species. Individually, both the mSCN and vSCN are similar to the mammalian SCN in terms of their connections. Based on these data and other studies, we present a working model of the avian SCN that includes both the mSCN and vSCN as hypothalamic oscillators. We contend that both structures are involved in a suprachiasmatic complex that, as a functional group, may be homologous to the mammalian SCN. PMID:16528725
Meningeal afferent signaling and the pathophysiology of migraine.
Burgos-Vega, Carolina; Moy, Jamie; Dussor, Gregory
Migraine is the most common neurological disorder. Attacks are complex and consist of multiple phases but are most commonly characterized by intense, unilateral, throbbing headache. The pathophysiology contributing to migraine is poorly understood and the disorder is not well managed with currently available therapeutics, often rendering patients disabled during attacks. The mechanisms most likely to contribute to the pain phase of migraine require activation of trigeminal afferent signaling from the cranial meninges and subsequent relay of nociceptive information into the central nervous system in a region of the dorsal brainstem known as the trigeminal nucleus caudalis. Events leading to activation of meningeal afferents are unclear, but nerve endings within this tissue are mechanosensitive and also express a variety of ion channels including acid-sensing ion channels and transient receptor-potential channels. These properties may provide clues into the pathophysiology of migraine by suggesting that decreased extracellular pH and environmental irritant exposure in the meninges contributes to headache. Neuroplasticity is also likely to play a role in migraine given that attacks are triggered by routine events that are typically nonnoxious in healthy patients and clear evidence of sensitization occurs during an attack. Where and how plasticity develops is also not clear but may include events directly on the afferents and/or within the TNC. Among the mediators potentially contributing to plasticity, calcitonin gene-related peptide has received the most attention within the migraine field but other mechanisms may also contribute. Ultimately, greater understanding of the molecules and mechanisms contributing to migraine will undoubtedly lead to better therapeutics and relief for the large number of patients across the globe who suffer from this highly disabling neurological disorder. PMID:25744685
Imaging stretch-activated firing of spinal afferent nerve endings in mouse colon.
Travis, Lee; Spencer, Nick J
Spinal afferent neurons play a major role in detecting noxious and innocuous stimuli from visceral organs, such as the gastrointestinal tract. However, all our understanding about spinal afferents has been obtained from recordings of spinal afferent axons, or cell bodies that lie outside the gut wall, or peripheral organ they innervate. No recordings have been made directly from spinal afferent nerve endings, which is where sensory transduction occurs. We developed a preparation whereby recordings could be made from rectal afferent nerve endings in the colon, to characterize mechanisms underlying sensory transduction. Dorsal root ganglia (L6-S2) were removed from mice, whilst retaining neural continuity with the colon. Fluo-4-AM was used to record from rectal afferent nerve endings in myenteric ganglia and circular muscle at 36°C. In slack (unstretched) preparations of colon, no calcium transients were recorded from spinal afferent endings. However, in response to a maintained increase in circumferential diameter, a maintained discharge of calcium transients occurred simultaneously in multiple discrete varicosities along single axons of rectal afferents in myenteric ganglia and circular muscle. Stretch-activated calcium transients were resistant to hexamethonium and nifedipine, but were abolished by tetrodotoxin, CPA, BAPTA-AM, cobalt, gadolinium, or replacement of extracellular Na(+) with NMDG. In summary, we present a novel preparation in which stretch-activated firing of spinal afferent nerve endings can be recorded, using calcium imaging. We show that circumferential stretch of the colon activates a maintained discharge of calcium transients simultaneously in varicosities along single rectal afferent endings in myenteric ganglia and circular muscle. Non-selective cation channels, TTX-sensitive Na(+) channels and both extracellular calcium influx and intracellular Ca(2+) stores are required for stretch-activated calcium transients in rectal afferent endings. PMID:24109427
Sensitivity of rat temporalis muscle afferent fibers to peripheral N-methyl-D-aspartate receptor activation.
Dong, X D; Mann, M K; Sessle, B J; Arendt-Nielsen, L; Svensson, P; Cairns, B E
The temporalis muscle is a common source of pain in headache and chronic craniofacial pain conditions such as temporomandibular disorders, which have an increased prevalence in women. The characteristics of slowly conducting temporalis afferent fibers have not been investigated. Therefore, the aim of the present study was to examine the characteristics of slowly conducting temporalis muscle afferent fibers and to determine whether these fibers are excited by activation of peripheral N-methyl-D-aspartate receptors. The response properties of a total of 117 temporalis afferent fibers were assessed in male and female rats. A majority of these fibers had high mechanical thresholds and slow conduction velocities (<10 m/s). The mechanical threshold of the temporalis afferent fibers was inversely correlated with afferent conduction velocity, however, no sex-related differences in mechanical threshold were identified. There were also no sex-related differences in N-methyl-D-aspartate-evoked afferent discharge. Indeed, injection of a high concentration (1600 mM) of N-methyl-D-aspartate into the temporalis muscle was necessary to evoke significant afferent discharge. Thirty minutes after the initial injection of N-methyl-D-aspartate into the temporalis muscle, a second injection of N-methyl-D-aspartate produced a response only about 50% as large as the initial injection. Co-injection of ketamine (20 mM) with the second injection of N-methyl-D-aspartate significantly decreased N-methyl-D-aspartate-evoked afferent discharge in both sexes. This concentration of ketamine is greater than that needed to attenuate afferent discharge evoked by injection of glutamate into the masseter muscle. These results suggest that unlike masseter afferent fibers, temporalis afferent fibers are relatively insensitive to peripheral N-methyl-D-aspartate receptor activation. PMID:16716525
Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis
Yoshimura, Naoki; Oguchi, Tomohiko; Yokoyama, Hitoshi; Funahashi, Yasuhito; Yoshikawa, Satoru; Sugino, Yoshio; Kawamorita, Naoki; Kashyap, Mahendra P; Chancellor, Michael B; Tyagi, Pradeep; Ogawa, Teruyuki
Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis. PMID:24807488
Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling.
Lüscher, Christian; Malenka, Robert C
Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior. PMID:21338877
Erk1/2 inhibit synaptic vesicle exocytosis through L type calcium channels
Subramanian, Jaichandar; Morozov, Alexei
L type calcium channels play only a minor role in basal neurotransmitter release in brain neurons, but contribute significantly after induction of plasticity. Very little is known about mechanisms that enable L type calcium channel participation in neurotransmitter release. Here, using mouse primary cortical neurons, we found that inhibition of Erk1/2 enhanced synaptic vesicle exocytosis by increasing calcium influx through L type calcium channels. Furthermore, inhibition of Erk1/2 increased the surface fraction of these channels. These findings indicate a novel inhibitory effect of Erk1/2 on synaptic transmission through L type calcium channels. PMID:21430174
Rectal afferent function in patients with inflammatory and functional intestinal disorders
Charles N. Bernstein; Negar Niazi; Marie Robert; Howard Mertz; Anatoly Kodner; Julie Munakata; Bruce Naliboff; Emeran A. Mayer
Chronic symptoms of abdominal pain and discomfort are reported by patients with inflammatory bowel disease (IBD) and functional disorders of the gut, such as Irritable Bowel Syndrome (IBS). It has recently been suggested that transient inflammatory mucosal events may result in long-lasting sensitization of visceral afferent pathways. To determine the effect of recurring intestinal tissue irritation on lumbosacral afferent pathways,
Formation of dendritic spines in cultured striatal neurons depends on excitatory afferent activity
Segal, Menahem
Formation of dendritic spines in cultured striatal neurons depends on excitatory afferent activity of afferent innervation in the formation of dendritic spines was studied in cultured rat striatum and were virtually devoid of dendritic spines. Adding GFP-expressing mouse cortical neurons to the striatal
Cortical and subcortical afferents to the amygdala of the rhesus monkey (Macaca mulatta)
SUMMARY The afferent projections to the primate amygdala were studied using horseradish peroxidase. The potential advantages of this technique are discussed compared with those previously used to determine amygdaloid afferents. The findings indicate that certain agranular or dysgranular cortical regions may project directly to the amygdala: in particular, the orbital frontal cortex, anterior cingulate gyrus, subcallosal gyrus, temporal pole and
Glutamate exocytosis from astrocytes controls synaptic strength
Newman, Eric A.
control of synaptic activity via exocytosis of glutamate from astrocytes. Brain communication viaGlutamate exocytosis from astrocytes controls synaptic strength Pascal Jourdain1,6, Linda H we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer
Spontaneous vesicle recycling in the synaptic bouton
Truckenbrodt, Sven; Rizzoli, Silvio O.
The trigger for synaptic vesicle exocytosis is Ca2+, which enters the synaptic bouton following action potential stimulation. However, spontaneous release of neurotransmitter also occurs in the absence of stimulation in virtually all synaptic boutons. It has long been thought that this represents exocytosis driven by fluctuations in local Ca2+ levels. The vesicles responding to these fluctuations are thought to be the same ones that release upon stimulation, albeit potentially triggered by different Ca2+ sensors. This view has been challenged by several recent works, which have suggested that spontaneous release is driven by a separate pool of synaptic vesicles. Numerous articles appeared during the last few years in support of each of these hypotheses, and it has been challenging to bring them into accord. We speculate here on the origins of this controversy, and propose a solution that is related to developmental effects. Constitutive membrane traffic, needed for the biogenesis of vesicles and synapses, is responsible for high levels of spontaneous membrane fusion in young neurons, probably independent of Ca2+. The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs) rather than bona fide synaptic vesicles. In mature neurons, constitutive traffic is much dampened, and the few remaining spontaneous release events probably represent bona fide spontaneously releasing synaptic vesicles (SRSVs) responding to Ca2+ fluctuations, along with a handful of CRVs that participate in synaptic vesicle turnover. PMID:25538561
Temporal dynamics of L5 dendrites in medial prefrontal cortex regulate integration versus coincidence detection of afferent inputs.
Dembrow, Nikolai C; Zemelman, Boris V; Johnston, Daniel
Distinct brain regions are highly interconnected via long-range projections. How this inter-regional communication occurs depends not only upon which subsets of postsynaptic neurons receive input, but also, and equally importantly, upon what cellular subcompartments the projections target. Neocortical pyramidal neurons receive input onto their apical dendrites. However, physiological characterization of these inputs thus far has been exclusively somatocentric, leaving how the dendrites respond to spatial and temporal patterns of input unexplored. Here we used a combination of optogenetics with multisite electrode recordings to simultaneously measure dendritic and somatic responses to afferent fiber activation in two different populations of layer 5 (L5) pyramidal neurons in the rat medial prefrontal cortex (mPFC). We found that commissural inputs evoked monosynaptic responses in both intratelencephalic (IT) and pyramidal tract (PT) dendrites, whereas monosynaptic hippocampal input primarily targeted IT, but not PT, dendrites. To understand the role of dendritic integration in the processing of long-range inputs, we used dynamic clamp to simulate synaptic currents in the dendrites. IT dendrites functioned as temporal integrators that were particularly responsive to dendritic inputs within the gamma frequency range (40-140 Hz). In contrast, PT dendrites acted as coincidence detectors by responding to spatially distributed signals within a narrow time window. Thus, the PFC extracts information from different brain regions through the combination of selective dendritic targeting and the distinct dendritic physiological properties of L5 pyramidal dendrites. PMID:25788669
Copper signaling in the mammalian nervous system: synaptic effects
Gaier, ED; Eipper, BA; Mains, RE
Copper (Cu) is an essential metal present at high levels in the CNS. Its role as a co-factor in mitochondrial ATP production and in other essential cuproenzymes is well defined. Menkes and Wilson's diseases are severe neurodegenerative conditions that demonstrate the importance of Cu transport into the secretory pathway. Brain levels of Cu, which is almost entirely protein bound, exceed extracellular levels by more than a hundred-fold. Cu stored in the secretory pathway is released in a Ca2+-dependent manner and can transiently reach concentrations over 100 µM at synapses. The ability of low µM levels of Cu to bind to and modulate the function of ?-aminobutyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA) receptors and voltage-gated Ca2+ channels contributes to its effects on synaptic transmission. Cu also binds to amyloid precursor protein and prion protein; both proteins are found at synapses and brain Cu homeostasis is disrupted in mice lacking either protein. Especially intriguing is the ability of Cu to affect AMP-activated protein kinase (AMPK), a monitor of cellular energy status. Despite this, few investigators have examined the direct effects of Cu on synaptic transmission and plasticity. Although the variability of results demonstrates complex influences of Cu that are highly method-sensitive, these studies nevertheless strongly support important roles for endogenous Cu and new roles for Cu-binding proteins in synaptic function/plasticity and behavior. Further study of the many roles of Cu in nervous system function will reveal targets for intervention in other diseases in which Cu homeostasis is disrupted. PMID:23115049
Plasmacytoid dendritic cells migrate in afferent skin lymph.
Pascale, Florentina; Pascale, Florentia; Contreras, Vanessa; Bonneau, Michel; Courbet, Alexandre; Chilmonczyk, Stefan; Bevilacqua, Claudia; Epardaud, Mathieu; Eparaud, Mathieu; Niborski, Violeta; Riffault, Sabine; Balazuc, Anne-Marie; Foulon, Eliane; Guzylack-Piriou, Laurence; Riteau, Beatrice; Hope, Jayne; Bertho, Nicolas; Charley, Bernard; Schwartz-Cornil, Isabelle
Conventional dendritic cells enter lymph nodes by migrating from peripheral tissues via the lymphatic route, whereas plasmacytoid dendritic cells (pDC), also called IFN-producing cells (IPC), are described to gain nodes from blood via the high endothelial venules. We demonstrate here that IPC/pDC migrate in the afferent lymph of two large mammals. In sheep, injection of type A CpG oligodinucleotide (ODN) induced lymph cells to produce type I IFN. Furthermore, low-density lymph cells collected at steady state produced type I IFN after stimulation with type A CpG ODN and enveloped viruses. Sheep lymph IPC were found within a minor B(neg)CD11c(neg) subset expressing CD45RB. They presented a plasmacytoid morphology, expressed high levels of TLR-7, TLR-9, and IFN regulatory factor 7 mRNA, induced IFN-gamma production in allogeneic CD4(pos) T cells, and differentiated into dendritic cell-like cells under viral stimulation, thus fulfilling criteria of bona fide pDC. In mini-pig, a CD4(pos)SIRP(pos) subset in afferent lymph cells, corresponding to pDC homologs, produced type I IFN after type A CpG-ODN triggering. Thus, pDC can link innate and acquired immunity by migrating from tissue to draining node via lymph, similarly to conventional dendritic cells. PMID:18424716
State-space decoding of primary afferent neuron firing rates
Wagenaar, JB; Ventura, V; Weber, DJ
Kinematic state feedback is important for neuroprostheses to generate stable and adaptive movements of an extremity. State information, represented in the firing rates of populations of primary afferent neurons, can be recorded at the level of the dorsal root ganglia (DRG). Previous work in cats showed the feasibility of using DRG recordings to predict the kinematic state of the hind limb using reverse regression. Although accurate decoding results were attained, reverse regression does not make efficient use of the information embedded in the firing rates of the neural population. In this paper, we present decoding results based on state-space modeling, and show that it is a more principled and more efficient method for decoding the firing rates in an ensemble of primary afferent neurons. In particular, we show that we can extract confounded information from neurons that respond to multiple kinematic parameters, and that including velocity components in the firing rate models significantly increases the accuracy of the decoded trajectory. We show that, on average, state-space decoding is twice as efficient as reverse regression for decoding joint and endpoint kinematics. PMID:21245525
Laryngeal afferent activity and reflexes in the guinea pig.
Tsubone, H; Sant'Ambrogio, G; Anderson, J W; Orani, G P
We have investigated the various sensory modalities represented in the laryngeal nerves of the guinea pig. In addition, we have examined the defensive responses to mechanical stimuli and capsaicin instillation into the laryngeal lumen of the same species. Recording from both the whole superior laryngeal nerve and from single units of the same nerve revealed the presence of afferent activity related (1) to the contraction of laryngeal muscles and/or the 'tracheal tug', (2) to transmural pressure changes, either positive or negative and (3) to mechanical and chemical irritants. The irritant type receptors of this species, when challenged with water solutions, show two distinct patterns of activation: some behave as osmoreceptors, some respond to the lack of chloride ions. Challenges with capsaicin solutions activated one ending with the characteristics of a C-fiber receptor that failed to respond to a subsequent trial. This behavior is consistent with the reflex apnea, dependent on an intact laryngeal innervation, induced by capsaicin instillation that was not elicitable on repeating the challenge. Cough to mechanical probing of the supraglottic area depended on an intact SLN, whereas cough elicited from the subglottic area depended on an intact RLN. Cough to mechanical stimulation could not be desensitized by capsaicin. These findings suggest the presence of two independent afferent pathways for defensive responses. PMID:1780601
A number of environmental chemicals have been reported to alter thyroid hormone (TH) function. It is well established that severe hypothyroidism during critical periods of brain development leads to alterations in hippocampal structure and learning deficits, yet evaluation of ...
Endocannabinoid-mediated retrograde modulation of synaptic transmission.
Ohno-Shosaku, Takako; Kano, Masanobu
One of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), serves as a retrograde messenger at various types of synapses throughout the brain. Upon postsynaptic activation, 2-AG is released immediately after de novo synthesis, activates presynaptic CB1 cannabinoid receptors, and transiently suppresses neurotransmitter release. When CB1 receptor activation is combined with some other factors such as presynaptic activity, the suppression is converted to a long-lasting form. Whereas 2-AG primarily transmits a rapid, transient, point-to-point retrograde signal, the other major endocannabinoid, anandamide, may function as a relatively slow retrograde or non-retrograde signal or as an agonist of the vanilloid receptor. The endocannabinoid system can be up- or down-regulated by a variety of physiological and environmental factors including stress, which might be clinically important. PMID:24747340
Role of AMPA Receptor Cycling in Synaptic Transmission and Plasticity
Christian Lüscher; Houhui Xia; Eric C Beattie; Reed C Carroll; Mark von Zastrow; Robert C Malenka; Roger A Nicoll
Compounds known to disrupt exocytosis or endocytosis were introduced into CA1 pyramidal cells while monitoring excitatory postsynaptic currents (EPSCs). Disrupting exocytosis or the interaction of GluR2 with NSF caused a gradual reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC but prevented the
Serotonin and Synaptic Transmission at Invertebrate Neuromuscular Junctions
Wu, Wen-Hui
The serotonergic system in vertebrates and invertebrates has been a focus for over 50 years and will likely continue in the future. Recently, genomic analysis and discovery of alternative splicing and differential expression in tissues have increased the knowledge of serotonin (5-HT) receptor types. Comparative studies can provide useful insights to the wide variety of mechanistic actions of 5-HT responsible for behaviors regulated or modified by 5-HT. To determine cellular responses and influences on neural systems as well as the efferent control of behaviors by the motor units, preparations amenable to detailed studies of synapses are beneficial as working models. The invertebrate neuromuscular junctions (NMJs) offer some unique advantages for such investigations; action of 5-HT at crustacean NMJs has been widely studied, and leech and Aplysia continue to be key organisms. However, there are few studies in insects likely due to the focus in modulation within the CNS and lack of evidence of substantial action of 5-HT at the Drosophila NMJs. There are only a few reports in gastropods and annelids as well as other invertebrates. In this review we highlight some of the key findings of 5-HT actions and receptor types associated at NMJs in a variety of invertebrate preparations in hopes that future studies will build on this knowledge base. PMID:23055788
NSF Binding to GluR2 Regulates Synaptic Transmission
Atsushi Nishimune; John T. R Isaac; Elek Molnar; Jacques Noel; S. Russell Nash; Mitsuo Tagaya; Graham L Collingridge; Shigetada Nakanishi; Jeremy M Henley
Here, we show that N-ethylmaleimide–sensitive fusion protein (NSF) interacts directly and selectively with the intracellular C-terminal domain of the GluR2 subunit of AMPA receptors. The interaction requires all three domains of NSF but occurs between residues Lys-844 and Gln-853 of rat GluR2, with Asn-851 playing a critical role. Loading of decapeptides corresponding to the NSF-binding domain of GluR2 into rat
Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.
Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G
Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons. PMID:25573367
Non-synaptic transmission at autonomic neuroeffector junctions Geoffrey Burnstock *
Burnstock, Geoffrey
cells, receptors for neurotransmitters accumulate on cell membranes at close junctions; muscle effectors are bundles rather than single smooth muscle cells, that are connected by gap junctions which allow, the effectors are muscle bundles rather than single smooth muscle cells, which are connected by low
Non-synaptic transmission at autonomic neuroeffector junctions Geoffrey Burnstock *
Burnstock, Geoffrey
on cell membranes at close junctions; muscle effectors are bundles rather than single smooth muscle cells muscle cells, which are connected by low-resistance pathways (gap junctions) that allow electrotonic the varicosities are con- tinuously moving and their special relation with muscle cell membranes changes with time
Learning and reconsolidation implicate different synaptic mechanisms
Li, Yan; Meloni, Edward G.; Carlezon, William A.; Milad, Mohammed R.; Pitman, Roger K.; Nader, Karim; Bolshakov, Vadim Y.
Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning–induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning–induced synaptic enhancements mediating fear memory reconsolidation. PMID:23487762
Learning and reconsolidation implicate different synaptic mechanisms.
Li, Yan; Meloni, Edward G; Carlezon, William A; Milad, Mohammed R; Pitman, Roger K; Nader, Karim; Bolshakov, Vadim Y
Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning-induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning-induced synaptic enhancements mediating fear memory reconsolidation. PMID:23487762
Total Reconstruction of the Afferent Loop for Treatment of Radiation-Induced Afferent Loop Obstruction with Segmental Involvement after Pancreaticoduodenectomy with Roux-en-Y Reconstruction
Blouhos, Konstantinos; Boulas, Konstantinos A.; Salpigktidis, Ilias I.; Konstantinidou, Anna; Ioannidis, Konstantinos; Hatzigeorgiadis, Anestis
As the literature on afferent loop obstruction (ALO) after pancreaticoduodenectomy (PD) is very limited, standardized rules for its management do not exist. Herein, we report the case of a 65-year-old male patient with chronic ALO who had undergone PD with single Roux-en-Y limb reconstruction and adjuvant chemoradiation therapy for pancreatic head adenocarcinoma 2 years earlier. The patient was brought to the operating room with the diagnosis of radiation enteritis of the afferent loop with segmental involvement and concurrent hepaticojejunostomy (HJ) and pancreaticojejunostomy (PJ) stricture. Complete mobilization of the afferent loop, removal of the affected segment and reconstruction were performed. Reconstruction of the afferent loop was a one-way option for the surgeons because the Roux-en-Y reconstruction limited endoscopic access to the afferent loop, and the segmental radiation injury of the afferent loop ruled out bypass surgery. However, mobilization of the affected segment through a field of dense adhesions and revision of the HJ and PJ were technically demanding. PMID:24019782
Total Reconstruction of the Afferent Loop for Treatment of Radiation-Induced Afferent Loop Obstruction with Segmental Involvement after Pancreaticoduodenectomy with Roux-en-Y Reconstruction.
Blouhos, Konstantinos; Boulas, Konstantinos A; Salpigktidis, Ilias I; Konstantinidou, Anna; Ioannidis, Konstantinos; Hatzigeorgiadis, Anestis
As the literature on afferent loop obstruction (ALO) after pancreaticoduodenectomy (PD) is very limited, standardized rules for its management do not exist. Herein, we report the case of a 65-year-old male patient with chronic ALO who had undergone PD with single Roux-en-Y limb reconstruction and adjuvant chemoradiation therapy for pancreatic head adenocarcinoma 2 years earlier. The patient was brought to the operating room with the diagnosis of radiation enteritis of the afferent loop with segmental involvement and concurrent hepaticojejunostomy (HJ) and pancreaticojejunostomy (PJ) stricture. Complete mobilization of the afferent loop, removal of the affected segment and reconstruction were performed. Reconstruction of the afferent loop was a one-way option for the surgeons because the Roux-en-Y reconstruction limited endoscopic access to the afferent loop, and the segmental radiation injury of the afferent loop ruled out bypass surgery. However, mobilization of the affected segment through a field of dense adhesions and revision of the HJ and PJ were technically demanding. PMID:24019782
Synaptic modulation via basolateral amygdala on the rat hippocampus-medial prefrontal cortex pathway in fear extinction.
Inoue, Sumitaka; Kamiyama, Hidekazu; Matsumoto, Machiko; Yanagawa, Yoshiki; Hiraide, Sachiko; Saito, Yasuhiro; Shimamura, Kei-ichi; Togashi, Hiroko
The present study elucidated the functional role of modulatory effects of basolateral amygdala (BLA) on synaptic transmission in the rat hippocampus-medial prefrontal cortex (mPFC) pathway, compared with the hippocampal dentate gyrus (DG). Exposure to conditioned fear stress (CFS) or prior BLA activation enhanced tetanus-induced long-term potentiation (LTP) in DG. A similar synaptic response was found by low frequency stimulation (LFS) prior to tetanus. In mPFC, they did not affect LTP, but prior BLA activation, as well as pretreatment with the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 (0.1 mg/kg, i.p.), suppressed LFS-primed LTP. This BLA-mediated synaptic pattern was mimicked by synaptic changes observed in the fear extinction process; prior BLA activation suppressed the synaptic potentiation responsible for extinction retrieval and attenuated decreases in fear-related freezing behavior. These data suggest that LFS-primed LTP in mPFC is related to the neural basis of extinction. Extinction-related synaptic potentiation did not occur in a juvenile stress model that exhibited extinction deficit. In addition, LFS-primed LTP was suppressed in this model, which was reversed by the NMDA-receptor agonist d-cycloserine (15 mg/kg, i.p.). These findings suggest that modulatory effects of BLA on synaptic function in the hippocampus-mPFC pathway play a significant role in fear extinction in rats. PMID:24189655
Activation of ERK signaling in rostral ventromedial medulla is dependent on afferent input from dorsal column pathway and contributes to acetic acid-induced visceral nociception.
Kang, Yi; Zhao, Yujie; Guo, Ruijuan; Zhang, Meijuan; Wang, Yue; Mu, Yonggao; Wu, Anshi; Yue, Yun; Wu, Jing; Wang, Yun
Several lines of evidence from both animal and clinical studies have demonstrated that dorsal column (DC) pathway plays a critical role in visceral pain transmission from the spinal cord to supraspinal center. The descending pain modulation pathway from the rostral ventromedial medulla (RVM) area has been implicated in visceral nociceptive neurotransmission. Previous studies have demonstrated that the multiple protein kinase signaling transduction cascades in the RVM area contribute to the descending facilitation of inflammatory pain and neuropathic pain. However, whether these signaling transduction pathways in the RVM area are triggered by the afferent visceral input from the DC pathway during acute visceral pain remains elusive. Here, we have tested the hypothesis that the afferent visceral stimuli from the DC pathway might induce the activation of extracellular signal-regulated protein kinase (ERK) signaling in the RVM area and contribute to the descending facilitation of neurotransmission in a rat model of visceral pain. Our results showed that acetic acid-induced visceral nociception produced a persistent activation of ERK in the RVM area and a microinjection of a mitogen-activated ERK kinase (MEK) inhibitor, U0126, into the RVM area significantly inhibited the visceral noxious stimulation-induced behaviors in rats. A microinjection of lidocaine into the nucleus gracilis (NG) also inhibited the activation of ERK in the RVM area. The current study indicates that activated ERK signaling pathway in the RVM area is dependent on afferent input from dorsal column pathway and may contribute to acetic acid-induced visceral nociception. PMID:23876632
Functional Architecture of Vestibular Primary Afferents From the Posterior Semicircular Canal of a Turtle, Pseudemys (Trachemys) scripta elegans
Physiological studies in many vertebrates indicate that vestibular primary afferents are not a homogeneous population. Such data raise the question of what structural mechanisms underlie these physiological differences and what functional role is played by afferents of each type. We have begun to answer these questions by characterizing the architecture of 110 afferents innervating the posterior canal of Pseudemys scripta.
Evidence that protons act as neurotransmitters at vestibular hair cell–calyx afferent synapses
Highstein, Stephen M.; Holstein, Gay R.; Mann, Mary Anne; Rabbitt, Richard D.
Present data support the conclusion that protons serve as an important neurotransmitter to convey excitatory stimuli from inner ear type I vestibular hair cells to postsynaptic calyx nerve terminals. Time-resolved pH imaging revealed stimulus-evoked extrusion of protons from hair cells and a subsequent buildup of [H+] within the confined chalice-shaped synaptic cleft (?pH ? ?0.2). Whole-cell voltage-clamp recordings revealed a concomitant nonquantal excitatory postsynaptic current in the calyx terminal that was causally modulated by cleft acidification. The time course of [H+] buildup limits the speed of this intercellular signaling mechanism, but for tonic signals such as gravity, protonergic transmission offers a significant metabolic advantage over quantal excitatory postsynaptic currents—an advantage that may have driven the proliferation of postsynaptic calyx terminals in the inner ear vestibular organs of contemporary amniotes. PMID:24706862
Gastric vagal afferent modulation by leptin is influenced by food intake status.
Kentish, Stephen J; O'Donnell, Tracey A; Isaacs, Nicole J; Young, Richard L; Li, Hui; Harrington, Andrea M; Brierley, Stuart M; Wittert, Gary A; Blackshaw, L Ashley; Page, Amanda J
Energy intake is strongly influenced by vagal afferent signals from the stomach, and is also modulated by leptin. Leptin may be secreted from gastric epithelial cells, so we aimed to determine the direct effect of leptin on gastric vagal afferents under different feeding conditions. Female C57BL/6 mice were fed standard laboratory diet, high-fat diet or were food restricted. The expression of leptin receptor (Lep-R) and its signal transduction molecules in vagal afferents was determined by retrograde tracing and reverse-transcription polymerase chain reaction, and the relationship between leptin-immunopositive cells and gastric vagal afferent endings determined by anterograde tracing and leptin immunohistochemistry. An in vitro preparation was used to determine the functional effects of leptin on gastric vagal afferents and the second messenger pathways involved. Leptin potentiated vagal mucosal afferent responses to tactile stimuli, and epithelial cells expressing leptin were found close to vagal mucosal endings. After fasting or diet-induced obesity, potentiation of mucosal afferents by leptin was lost and Lep-R expression reduced in the cell bodies of gastric mucosal afferents. These effects in diet-induced obese mice were accompanied by a reduction in anatomical vagal innervation of the gastric mucosa. In striking contrast, after fasting or diet-induced obesity, leptin actually inhibited responses to distension in tension receptors. The inhibitory effect on gastric tension receptors was mediated through phosphatidylinositol 3-kinase-dependent activation of large-conductance calcium-activated potassium channels. The excitatory effect of leptin on gastric mucosal vagal afferents was mediated by phospholipase C-dependent activation of canonical transient receptor potential channels. These data suggest the effect of leptin on gastric vagal afferent excitability is dynamic and related to the feeding state. Paradoxically, in obesity, leptin may reduce responses to gastric distension following food intake. PMID:23266933
Functional recovery of anterior semicircular canal afferents following hair cell regeneration in birds
NASA Technical Reports Server (NTRS)
Boyle, Richard; Highstein, Stephen M.; Carey, John P.; Xu, Jinping
Streptomycin sulfate (1.2 g/kg i.m.) was administered for 5 consecutive days to 5-7-day-old white Leghorn chicks; this causes damage to semicircular canal hair cells that ultimately regenerate to reform the sensory epithelium. During the recovery period, electrophysiological recordings were taken sequentially from anterior semicircular canal primary afferents using an indentation stimulus of the canal that has been shown to mimic rotational stimulation. Chicks were assigned to an early (14-18 days; n = 8), intermediate (28-34 days; n = 5), and late (38-58 days; n = 4) period based on days after treatment. Seven untreated chicks, 15-67 days old, provided control data. An absence of background and indent-induced discharge was the prominent feature of afferents in the early period: only "silent" afferents were encountered in 5/8 experiments. In several of these chicks, fascicles of afferent fibers were seen extending up to the epithelium that was void of hair cells, and intra- and extracellular biocytin labeling revealed afferent processes penetrating into the supporting cell layer of the crista. In 3/8 chicks 74 afferents could be characterized, and they significantly differed from controls (n = 130) by having a lower discharge rate and a negligible response to canal stimulation. In the intermediate period there was considerable variability in discharge properties of 121 afferents, but as a whole the number of "silent" fibers in the canal nerve diminished, the background rate increased, and a response to canal stimulation detected. Individually biocytin-labeled afferents had normal-appearing terminal specializations in the sensory epithelium by 28 days poststreptomycin. In the late period, afferents (n = 58) remained significantly different from controls in background discharge properties and response gain. The evidence suggests that a considerable amount of variability exists between chicks in the return of vestibular afferent function following ototoxic injury and that the secretory function of regenerating hair cells might become functional before their transducer function.
Dynamics of fast and slow inhibition from cerebellar golgi cells allow flexible control of synaptic integration.
Crowley, John J; Fioravante, Diasynou; Regehr, Wade G
Throughout the brain, multiple interneuron types influence distinct aspects of synaptic processing. Interneuron diversity can thereby promote differential firing from neurons receiving common excitation. In contrast, Golgi cells are the sole interneurons regulating granule cell spiking evoked by mossy fibers, thereby gating inputs to the cerebellar cortex. Here, we examine how this single interneuron class modifies activity in its targets. We find that GABA(A)-mediated transmission at unitary Golgi cell --> granule cell synapses consists of varying contributions of fast synaptic currents and sustained inhibition. Fast IPSCs depress and slow IPSCs gradually build during high-frequency Golgi cell activity. Consequently, fast and slow inhibition differentially influence granule cell spike timing during persistent mossy fiber input. Furthermore, slow inhibition reduces the gain of the mossy fiber --> granule cell input-output curve, while fast inhibition increases the threshold. Thus, a lack of interneuron diversity need not prevent flexible inhibitory control of synaptic processing. PMID:19778512
HDAC4 governs a transcriptional program essential for synaptic plasticity and memory
Sando, Richard; Gounko, Natalia; Pieraut, Simon; Liao, Lujian; Yates, John; Maximov, Anton
SUMMARY Neuronal activity influences genes involved in circuit development and information processing. However, the molecular basis of this process remains poorly understood. We found that HDAC4, a histone deacetylase that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and memory. The nuclear import of HDAC4 and its association with chromatin is negatively regulated by NMDA receptors. In the nucleus, HDAC4 represses genes encoding constituents of central synapses, thereby affecting synaptic architecture and strength. Furthermore, we show that a truncated form of HDAC4 encoded by an allele associated with mental retardation is a gain-of-function nuclear repressor that abolishes transcription and synaptic transmission despite the loss of the deacetylase domain. Accordingly, mice carrying a mutant that mimics this allele exhibit deficits in neurotransmission and spatial memory. These studies elucidate a mechanism of experience-dependent plasticity and define the biological role of HDAC4 in the brain. PMID:23141539
Synaptic Encoding of Fear Extinction in mPFC-amygdala Circuits
Cho, Jun-Hyeong; Deisseroth, Karl; Bolshakov, Vadim Y.
Retrieval of fear extinction memory is associated with increased firing of neurons in the medial prefrontal cortex (mPFC). It is unknown, however, how extinction learning-induced changes in mPFC activity are relayed to target structures in the amygdala, resulting in diminished fear responses. Here, we show that fear extinction decreases the efficacy of excitatory synaptic transmission in projections from the mPFC to the basolateral nucleus of the amygdala (BLA), whereas inhibitory responses are not altered. In contrast,synaptic strength at direct mPFC inputs to intercalated neurons remains unchanged following extinction. Moreover, priming stimulation of mPFC projections induced heterosynaptic inhibition in auditory cortical inputs to the BLA. These synaptic mechanisms could contribute to the encoding of extinction memory by diminishing the ability of projections from the mPFC to drive BLA activity while retaining the ability of intercalated neurons to inhibit the output nuclei of the amygdala. PMID:24290204
Synaptic potentiation onto habenula neurons in the learned helplessness model of depression
Li, B.; Schulz, D.; Li, B; Piriz, J.; Mirrione, M.; Chung, C.H.; Proulx, C.D.; Schulz, D.; Henn, F.; Malinow, R.
The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhan